Publications by authors named "Tomonobu Hasegawa"

273 Publications

The current status of 492 adult women with Turner syndrome: a questionnaire survey by the Foundation for Growth Science.

Endocr J 2021 Apr 28. Epub 2021 Apr 28.

Growth Hormone Therapy Research Committee, Foundation for Growth Science, Tokyo 113-0033, Japan.

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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http://dx.doi.org/10.1507/endocrj.EJ20-0617DOI Listing
April 2021

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

Endocrinol Diabetes Metab Case Rep 2021 Apr 1;2021. Epub 2021 Apr 1.

Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan.

Summary: 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.

Learning Points: Congenital NDI can present with neonatal hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib. Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.
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http://dx.doi.org/10.1530/EDM-20-0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115416PMC
April 2021

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

Clin Pediatr Endocrinol 2021 3;30(2):99-104. Epub 2021 Apr 3.

Department of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Aichi, Japan.

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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http://dx.doi.org/10.1297/cpe.30.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022032PMC
April 2021

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

J Pediatr Endocrinol Metab 2021 Mar 18;34(3):349-356. Epub 2020 Dec 18.

Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Japan.

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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http://dx.doi.org/10.1515/jpem-2020-0418DOI Listing
March 2021

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

J Pediatr Endocrinol Metab 2021 Mar 14;34(3):407-410. Epub 2020 Dec 14.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.1515/jpem-2020-0603DOI Listing
March 2021

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

Hum Genome Var 2021 Feb 3;8(1). Epub 2021 Feb 3.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

We report the first case of classic lipoid congenital adrenal hyperplasia and combined pituitary hormone deficiency. We identified pathogenic variants in the STAR gene: a novel variant of c.126_127delCCinsG, namely, p.Thr44Profs*2 and an already reported variant of c.634C>T, namely, p.Gln212*. The association with combined pituitary hormone deficiency might be just a coincidence.
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http://dx.doi.org/10.1038/s41439-021-00138-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859387PMC
February 2021

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

Front Pediatr 2020 13;8:569548. Epub 2021 Jan 13.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.3389/fped.2020.569548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838588PMC
January 2021

Clinical and Immunological Analyses of Ten Patients with MIRAGE Syndrome.

J Clin Immunol 2021 Apr 9;41(3):709-711. Epub 2021 Jan 9.

Department of Pediatrics, National Defense Medical College, Saitama, Japan.

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http://dx.doi.org/10.1007/s10875-020-00964-7DOI Listing
April 2021

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.

Am J Med Genet A 2021 04 5;185(4):1067-1075. Epub 2021 Jan 5.

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

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 (Sox9 ), 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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http://dx.doi.org/10.1002/ajmg.a.62063DOI Listing
April 2021

A novel mutation in the ACAN gene in a family with autosomal dominant short stature and intervertebral disc disease.

Hum Genome Var 2020 Dec 3;7(1):44. Epub 2020 Dec 3.

Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Heterozygous mutations in the ACAN gene have been reported in individuals with short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans. We report a family with a phenotypic constellation carrying a novel mutation in the ACAN gene. The proband was a 7-year-old Japanese girl with short stature. Her mother and maternal grandmother also had short stature and intervertebral disc disease. We analyzed the ACAN gene in the family and identified a novel heterozygous mutation: c.4634delT, Leu1545Profs*11.
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http://dx.doi.org/10.1038/s41439-020-00132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712780PMC
December 2020

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

J Clin Endocrinol Metab 2021 Mar;106(3):718-723

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

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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http://dx.doi.org/10.1210/clinem/dgaa893DOI Listing
March 2021

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

J Clin Endocrinol Metab 2021 Jan;106(1):e265-e272

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

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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http://dx.doi.org/10.1210/clinem/dgaa772DOI Listing
January 2021

Relapsing 6q24-related transient neonatal diabetes mellitus with insulin resistance: A case report.

Clin Pediatr Endocrinol 2020 3;29(4):179-182. Epub 2020 Oct 3.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

The overexpression of imprinted genes on chromosome 6q24 causes 6q24-related transient neonatal diabetes mellitus (6q24-TNDM). Most cases of 6q24-TNDM show transient diabetes mellitus (DM) during the neonatal period, followed by relapse after puberty. These two courses of DM are both characterized by insulin insufficiency. However, there has been no previously reported case of 6q24-TNDM with insulin resistance at relapse. We report the case of a 10-yr-old Japanese girl with relapsing 6q24-TNDM. In the neonatal period, she had hyperglycemia and was treated with insulin injection until 2 mo of age. After several years of remission of DM, her HbA1c level increased to 7.4% at 10 yr of age. Homeostasis model assessment of insulin resistance (HOMA-IR) score was high at 6.2. After starting metformin therapy, her glycemic control improved along with normalization of HOMA-IR score. Using microsatellite marker analysis on the 6q24 region and array comparative genome hybridization, we diagnosed her with 6q24-TNDM due to paternally inherited duplication of 6q24. These data indicate that patients with 6q24-TNDM can develop relapsing DM with insulin resistance.
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http://dx.doi.org/10.1297/cpe.29.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534527PMC
October 2020

A novel variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome.

Hum Genome Var 2020 28;7:30. Epub 2020 Sep 28.

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

We report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel variant, c.124delC, p.Leu42Cysfs*67.
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http://dx.doi.org/10.1038/s41439-020-00118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522263PMC
September 2020

Compound heterozygous variants in the gene in a Japanese girl with sitosterolemia.

Hum Genome Var 2020 14;7:25. Epub 2020 Sep 14.

Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.
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http://dx.doi.org/10.1038/s41439-020-00112-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490419PMC
September 2020

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

Clin Endocrinol (Oxf) 2021 Feb 20;94(2):229-236. Epub 2020 Oct 20.

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

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 (R  = .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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http://dx.doi.org/10.1111/cen.14347DOI Listing
February 2021

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

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

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

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

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

J Clin Endocrinol Metab 2020 11;105(11)

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

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

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

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

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

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

Clinical Features of 57 Patients with Lipoid Congenital Adrenal Hyperplasia: Criteria for Nonclassic Form Revisited.

J Clin Endocrinol Metab 2020 11;105(11)

Research Committee on Disorders of Adrenal Hormones, Research on Intractable Diseases, Health and Labour Sciences Research Grants, Tokyo, Japan.

Context: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. Classic (CLCAH) and nonclassic (NCLCAH) forms were reported as total and partial deficiencies, respectively, of adrenal and gonadal steroid hormones. The rarity of LCAH has precluded large-scale epidemiological and clinical investigations.

Objective: To determine the epidemiological and clinical characteristics of 2 forms of LCAH.

Design: A multicenter cross-sectional cohort study in Japan on December 1, 2017.

Participants: Fifty-seven patients with LCAH (median age, 23.7 years; range, 0.0-47.5 years).

Main Outcome Measures: Patient demographics, STAR genotype, Quigley grade, endocrinological and imaging data, treatment, and prognosis.

Results: Fifty-three and 4 patients fulfilled definite and probable diagnostic criteria for LCAH, respectively. When NCLCAH was defined as either Quigley grade 1 in XY karyotype, no episode of salt losing or requirement of fludrocortisone, or onset of primary adrenal insufficiency (PAI) at 1 year or older, patients were divided into groups of 43 patients with CLCAH (75.4%), 11 with NCLCAH (19.3%), and 3 with unclassified LCAH (5.3%). All of the patients with CLCAH and 7/11 NCLCAH (63.6%) were treated with fludrocortisone. CLCAH was diagnosed at a significantly younger age than NCLCAH (median, 0.0 vs 4.0 years). STAR-Arg272Cys or -Met225Thr was identified only in NCLCAH (8/11, 72.7%).

Conclusions: We demonstrated the relative proportions and clinical and molecular characteristics of NCLCAH and CLCAH in Japan. These criteria for NCLCAH correspond to all previously published cases and our cases whose masculinization of the external genitalia, ability of mineralocorticoid production, and onset of PAI were described.
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http://dx.doi.org/10.1210/clinem/dgaa557DOI Listing
November 2020

Congenital lipoid adrenal hyperplasia: Immunohistochemical study of testosterone synthesis in Leydig cells.

IJU Case Rep 2020 Mar 14;3(2):53-56. Epub 2020 Jan 14.

Department of Urology Fukushima Medical University School of Medicine Fukushima Japan.

Introduction: Congenital lipoid adrenal hyperplasia is a rare disease that causes disorders of sex development. The 46,XY patient presents with female external genitalia and inguinal testes. We describe the case of a patient with congenital lipoid adrenal hyperplasia and investigated the testes of this patient in detail.

Case Presentation: A 15-day-old 46,XY neonate presented with severe adrenal insufficiency. Congenital lipoid adrenal hyperplasia was diagnosed after detection of steroidogenic acute regulatory gene mutations. At 2 years and 5 months, she underwent bilateral gonadectomy. Leydig cells were observed both with and without lipid droplets in the testes of this patient. We also demonstrated immunohistochemically that some testosterone-synthesizing enzymes were maintained in this patient.

Conclusion: The results indicated transcription of testosterone-synthesizing enzymes remained despite lipid accumulation in this patient. The pattern of expression of testosterone-synthesizing enzymes suggested fetal Leydig cells may have remained after birth in the testes of this patient.
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http://dx.doi.org/10.1002/iju5.12142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292164PMC
March 2020

A novel mutation (p.Arg388Gln) in a patient with acromesomelic dysplasia, type Maroteaux.

Clin Pediatr Endocrinol 2020 11;29(3):99-103. Epub 2020 Jul 11.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Acromesomelic dysplasia, type Maroteaux (AMDM) is a congenital bone dysplasia characterized by disproportionate, acromesomelic shortening of the limbs and mild spondylar dysplasia. AMDM is caused by biallelic loss-of-function mutations in encoding natriuretic peptide receptor-B. We report on a 25-yr-old Japanese woman with AMDM. Her height was 119.0 cm (-7.4 SD) and weight 35 kg (-2.3 SD). She had acromesomelic shortening of limbs and severe brachydactyly. Radiological examination showed that her metacarpals and phalanges were short and wide, and her vertebral bodies were mildly flattened. Molecular analysis revealed a novel homozygous mutation (c.1163G>A, p.Arg388Gln). We performed functional studies using HA-tagged wild-type (WT) and Arg388Gln vectors (HA-WT-NPRB and HA-R388Q-NPRB). Cells expressing HA-R388Q-NPRB showed negligible cGMP responses to C-type natriuretic peptide (CNP) stimulation, indicating that the mutation led to severe loss-of-function. By immunofluorescence experiments under permeabilized conditions, HA-WT-NPRB was expressed on plasma membrane, while HA-R388Q-NPRB co-localized with an Endoplasmic Reticulum marker. Cells co-expressing R388Q and the WT exhibited lower responses under CNP treatment than cells co-expressing the WT and empty vectors. Thus, it was thought that R388Q caused a dominant-negative effect with a defect in cellular trafficking to the plasma membrane.
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http://dx.doi.org/10.1297/cpe.29.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348635PMC
July 2020

A phase I/IIa double blind single institute trial of low dose sirolimus for Pendred syndrome/DFNB4.

Medicine (Baltimore) 2020 May;99(19):e19763

Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.

Introduction: Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms.

Methods And Analysis: This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints.

Trial Registration Number: JMA-IIA00361; Pre-results.
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http://dx.doi.org/10.1097/MD.0000000000019763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220392PMC
May 2020

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

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

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

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

Infant with trisomy 13 who developed acute elevation of intraocular pressure and glaucoma.

Congenit Anom (Kyoto) 2020 Sep 3;60(5):151-152. Epub 2020 Feb 3.

Department of Pediatrics, Keio University, Tokyo, Japan.

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http://dx.doi.org/10.1111/cga.12367DOI Listing
September 2020

Reference values for salivary cortisol in healthy young infants by liquid chromatography-tandem mass spectrometry.

Pediatr Int 2020 Jul 22;62(7):785-788. Epub 2020 Jun 22.

Allergy Center, National Center for Child Health and Development, Tokyo, Japan.

Background: Sampling of salivary cortisol is non-invasive and important for the evaluation of the hypothalamic-pituitary-adrenal axis function and stress levels. However, the reference values for salivary cortisol measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in healthy infants are unclear. The aim of this study was to establish the reference values for salivary cortisol levels in healthy infants.

Methods: This study was a prospective observational cohort study following the participants until the age of 6 months. We analyzed 71 healthy, full-term infants at age 1 month between December 2017 and March 2018. We repeated saliva sampling every month, measured the salivary cortisol levels in the early morning by LC-MS/MS, and took the subjects' medical history by questionnaire.

Results: The minimum, 25th, 50th, 75th percentile, and maximum salivary cortisol levels were 0.08, 1.11, 2.21, 5.18, and 30.35 nmol/L, respectively.

Conclusions: We established the reference values for salivary cortisol in young infants using LC-MS/MS.
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http://dx.doi.org/10.1111/ped.14166DOI Listing
July 2020

Role of NPR2 mutation in idiopathic short stature: Identification of two novel mutations.

Mol Genet Genomic Med 2020 03 20;8(3):e1146. Epub 2020 Jan 20.

Department of Pediatrics, Hallym University College of Medicine, Chuncheoun, Korea.

Background: C-type natriuretic peptide (CNP, NPPC) and its receptor, natriuretic peptide receptor-B (NPR-B, NPR2), are critical for endochondral ossification. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. This study was performed to identify the NPR2 mutations in Korean patients with idiopathic short stature (ISS).

Methods: One hundred and sixteen subjects with nonsyndromic ISS were enrolled in this study, and the NPPC and NPR2 were sequenced. In silico prediction and in vitro functional analysis, using a cell-based assay, were performed to confirm their protein derangement.

Results: Mean age at diagnosis of ISS was 8.0 years, and the height z-score was -2.65. Three pathogenic variants (R921Q, R495C, and Y598N) and one benign variant (R787W) of the NPR2 were identified, while no novel sequence variant of the NPPC was found in all subjects. Two novel pathogenic mutants (R495C and Y598N) were predicted as highly pathogenic by several computational methods. In vitro study involving stimulation with CNP, R495C-, and Y598N-transfected cells showed decreased cGMP production compared to wild type-transfected cells.

Conclusion: Heterozygous NPR2 mutations were found in 2.6% of ISS Korean subjects. This prevalence and the dominant-negative effect of mutant NPR-B on growth signals imply that it is one of genetic causes of ISS.
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http://dx.doi.org/10.1002/mgg3.1146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057090PMC
March 2020

A neonatal case of HDR syndrome and a vascular ring with a novel mutation.

Hum Genome Var 2019 23;6:55. Epub 2019 Dec 23.

2Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo Japan.

HDR syndrome (OMIM #146255) is caused by haploinsufficiency of the gene. A vascular ring has not been reported in patients with -associated HDR syndrome. We report a neonatal case of HDR syndrome and a vascular ring that were possibly due to a novel frameshift mutation in the gene.
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http://dx.doi.org/10.1038/s41439-019-0087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928020PMC
December 2019