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Tsuyoshi Isojima,
Akira Shimatsu, Susumu Yokoya,
Kazuo Chihara,
Toshiaki Tanaka,
Naomi Hizuka,
Akira Teramoto,
Ke-Ita Tatsumi,
Katsuhiko Tachibana,
Noriyuki Katsumata,
Reiko Horikawa
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ABSTRACT: Measurements of insulin-like growth factor-I (IGF-I) are useful not only for diagnosis and management of patients with growth hormone (GH)-related disorders but also for assessing nutritional status. We reported population-based references of serum IGF-I in 1996. However, they did not properly reflect data in the transition period from puberty to maturity. The aim of the present study was to re-establish a set of normative data for IGF-I for the Japanese population. The study included 1,685 healthy Japanese subjects (845 males, 840 females) from 0 to 83 years old. Subjects suffering from diseases that could affect IGF-I levels were excluded. Obese or extremely thin adult subjects were also excluded. IGF-I concentrations were determined by commercially available immunoradiometric assays. The reference intervals were calculated using the LMS method. Median IGF-I levels reached 310 ng/mL in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years. The mean pretreatment IGF-1 SD scores in patients with severe GH deficiency (GHD) obtained from the database of the Foundation for Growth Science and from clinical studies for adult GHD were -2.1±1.6 and -4.9±2.5, respectively. The present study established age- and gender-specific normative IGF-I data for the Japanese population and showed the utility of these references for screening patients with severe GHD.
Endocrine Journal 05/2012; 59(9):771-80. · 2.03 Impact Factor
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Maki Fukami,
Makio Shozu,
Shun Soneda,
Fumiko Kato,
Akemi Inagaki,
Hiroshi Takagi,
Keiichi Hanaki,
Susumu Kanzaki,
Kenji Ohyama,
Tomoaki Sano,
Toshinori Nishigaki, Susumu Yokoya,
Gerhard Binder,
Reiko Horikawa,
Tsutomu Ogata
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ABSTRACT: Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by gynecomastia. Although cryptic inversions leading to abnormal fusions between CYP19A1 encoding aromatase and its neighboring genes have been identified in a few patients, the molecular basis remains largely unknown.
The objective of the study was to examine the genetic causes and phenotypic determinants in AEXS.
Eighteen affected males from six families participated in the study.
We identified three types of heterozygous genomic rearrangements, i.e. a 79,156-bp tandem duplication involving seven of 11 noncoding CYP19A1 exons 1, a 211,631-bp deletion involving exons 2-43 of DMXL2 and exons 5-10 of GLDN, and a 165,901-bp deletion involving exons 2-43 of DMXL2. The duplicated exon 1 functioned as transcription start sites, and the two types of deletions produced the same chimeric mRNA consisting of DMXL2 exon 1 and CYP19A1 coding exons. The DMXL2 exon 1 harbored a translation start codon, and the DMXL2/CYP19A1 chimeric mRNA was identified in only 2-5% of CYP19A1-positive transcripts. This was in contrast to the inversion-mediated chimeric mRNA that had no coding sequence on the fused exon 1 and accounted for greater than 80% of CYP19A1-positive transcripts. CYP19A1 was expressed in a limited number of tissues, whereas its neighboring genes involved in the chimeric mRNA formation were expressed widely.
This study provides novel mechanisms leading to gain of function of CYP19A1. Furthermore, it appears that clinical severity of AEXS is primarily determined by the tissue expression pattern of relevant genes and by the structural property of promoter-associated exons of chimeric mRNA.
The Journal of clinical endocrinology and metabolism 04/2011; 96(6):E1035-43. · 6.50 Impact Factor
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ABSTRACT: To investigate the long-term efficacy and safety of two doses (33 and 67 μg/kg/day) of growth hormone (GH) in short Japanese children born small for gestational age (SGA).
96 children born SGA (age 3 to <8 years) were randomized to GH at 33 or 67 μg/kg/day for 104 weeks, or to an untreated control (UC) group for 52 weeks. After 52 weeks, the UC group was randomized to GH at a dose of 33 or 67 μg/kg/day for a 156-week extension study. Initial treatment groups continued unchanged for the extension phase. Efficacy was evaluated by change in height SDS for chronological age from baseline to 208/260 weeks.
After 208 weeks, change in height SDS from baseline (least square (LS) means (SE)) was 1.01 (0.47) and 1.99 (0.67) in the UC 33 and UC 67 μg/kg/day groups, respectively. After 260 weeks, change in height SDS from baseline was 1.22 (0.51) and 2.01 (0.64) in the 33 and 67 μg/kg/day groups, respectively. Insulin-like growth factor-1 levels were significantly higher in the groups receiving 67 μg/kg/day but largely remained within normal limits (-2 to +2 SDS).
Long-term continuous GH treatment was well tolerated and effective in improving height SDS. Improvements were dose-dependent and significantly higher at 67 than 33 μg/kg/day.
Hormone Research in Paediatrics 01/2011; 76(6):411-8.
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Sumito Dateki,
Maki Fukami,
Ayumi Uematsu,
Masayuki Kaji,
Manami Iso,
Makoto Ono,
Michiyo Mizota, Susumu Yokoya,
Katsuaki Motomura,
Eiichi Kinoshita,
Hiroyuki Moriuchi,
Tsutomu Ogata
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ABSTRACT: Mutations of multiple transcription factor genes involved in pituitary development have been identified in a minor portion of patients with combined pituitary hormone deficiency (CPHD). However, copy number aberrations involving such genes have been poorly investigated in patients with CPHD.
We aimed to report the results of mutation and gene copy number analyses in patients with CPHD.
Seventy-one Japanese patients with CPHD were examined for mutations and gene copy number aberrations affecting POU1F1, PROP1, HESX1, LHX3, LHX4, and SOX3 by PCR-direct sequencing and multiplex ligation-dependent probe amplification. When a deletion was indicated, it was further studied by fluorescence in situ hybridization, oligoarray comparative genomic hybridization, and serial sequencing for long PCR products encompassing the deletion junction.
We identified a de novo heterozygous 522,009-bp deletion involving LHX4 in a patient with CPHD (GH, TSH, PRL, LH, and FSH deficiencies), anterior pituitary hypoplasia, ectopic posterior pituitary, and underdeveloped sella turcica. We also identified five novel heterozygous missense substitutions (p.V201I and p.H387P in LHX4, p.T63M and p.A322T in LHX3, and p.V53L in SOX3) that were assessed as rare variants by sequencing analyses for control subjects and available parents and by functional studies and in silico analyses.
The results imply the rarity of abnormalities affecting the six genes in patients with CPHD and the significance of the gene copy number analysis in such patients.
The Journal of clinical endocrinology and metabolism 08/2010; 95(8):4043-7. · 6.50 Impact Factor
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Sumito Dateki,
Kitaro Kosaka,
Kosei Hasegawa,
Hiroyuki Tanaka,
Noriyuki Azuma, Susumu Yokoya,
Koji Muroya,
Masanori Adachi,
Toshihiro Tajima,
Katsuaki Motomura,
Eiichi Kinoshita,
Hiroyuki Moriuchi,
Naoko Sato,
Maki Fukami,
Tsutomu Ogata
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ABSTRACT: Context: Although recent studies have suggested a positive role of OTX2 in pituitary as well as ocular development and function, detailed pituitary phenotypes in OTX2 mutations and OTX2 target genes for pituitary function other than HESX1 and POU1F1 remain to be determined. Objective: We aimed to examine such unresolved issues. Subjects: We studied 94 Japanese patients with various ocular or pituitary abnormalities. Results: We identified heterozygous p.K74fsX103 in case 1, p.A72fsX86 in case 2, p.G188X in two unrelated cases (3 and 4), and a 2,860,561-bp microdeletion involving OTX2 in case 5. Clinical studies revealed isolated GH deficiency in cases 1 and 5; combined pituitary hormone deficiency in case 3; abnormal pituitary structures in cases 1, 3, and 5; and apparently normal pituitary function in cases 2 and 4, together with ocular anomalies in cases 1-5. The wild-type Orthodenticle homeobox 2 (OTX2) protein transactivated the GNRH1 promoter as well as the HESX1, POU1F1, and IRBP (interstitial retinoid-binding protein) promoters, whereas the p.K74fsX103-OTX2 and p.A72fsX86-OTX2 proteins had no transactivation functions and the p.G188X-OTX2 protein had reduced ( approximately 50%) transactivation functions for the four promoters, with no dominant-negative effect. cDNA screening identified positive OTX2 expression in the hypothalamus. Conclusions: The results imply that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations, and that OTX2 can transactivate GNRH1 as well as HESX1 and POU1F1.
The Journal of clinical endocrinology and metabolism 12/2009; 95(2):756-64. · 6.50 Impact Factor
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ABSTRACT: Currently used growth charts for Japanese girls with Turner syndrome (TS) were constructed with auxological data obtained before the secular trend in growth reached a plateau. These charts were published in 1992 and may no longer be valid for the evaluation of stature and growth in girls with TS in clinical settings. Thus, we need to establish new clinical growth charts.
The samples for analysis were obtained by a retrospective cohort study. A total of 1867 Japanese girls with TS were registered between 1991 and 2004 for growth hormone (GH) treatment and their pretreatment anthropometric measurements were obtained. Reference growth charts were newly constructed using the LMS method from 1447 girls' cross-sectional data after exclusion of measurements derived from those with the presence of puberty, with previous growth-promoting treatment, or without cytogenetic evidence of TS.
The new clinical reference growth charts differ from the old charts. Secular trends can be detected in both height and weight. Mean adult height on the new chart is 141.2 cm, 3.0 cm taller than the old data. This result seems attributable to the secular trend observed during the same period in Japanese women.
The newly constructed clinical reference growth charts for Japanese girls with TS seem to be better for the evaluation of growth in girls with TS born after approximately 1970, although selection bias and some other limitations in the present study should be kept in mind.
Pediatrics International 04/2009; 51(5):709-14. · 0.63 Impact Factor
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ABSTRACT: To evaluate the prevalence of overweight in girls with Turner syndrome (TS) as classified by the two major anthropometric indices, body mass index (BMI) and weight-for-height (WFH) and to make growth reference charts of them for comparison with those of the normal population.
The samples for analysis were obtained from a retrospective cohort. In total, 1447 girls' cross-sectional data were analysed. Subjects were divided into four groups by ages: group A (0-5.99 years), B (6-10.99 years), C (11-15.99 years) and D (16-20.99 years). The cut-off values of overweight by BMI and WFH were those of the 90th percentile and 120 percent, respectively and the prevalence was calculated. For constructing growth reference charts, the LMS method was used.
The prevalence of overweight differed between the two indices. The proportions of the coincidental classification in all subjects, group A, B, C and D were 82.53%, 89.96%, 91.79%, 69.98% and 60.61%, respectively. These differences corresponded to the difference of age-dependent patterns of the two indices from those of the normal population, as judged from the growth charts constructed with all subjects.
A discrepancy in the prevalence of overweight as classified by BMI and WFH for girls with TS was detected.
Acta Paediatrica 12/2008; 98(3):513-8. · 2.07 Impact Factor
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ABSTRACT: The purpose of this study is to evaluate the trends in age and anthropometric data for girls with Turner syndrome (TS) at start of growth hormone (GH) treatment in Japan. The data for analysis were obtained from a retrospective cohort, the Foundation for Growth Science, Japan. We analyzed trends in starting age of GH treatment for girls with TS in Japan after dividing subjects (n=1,478) into three registration periods: 1991-1994, 1995-1999 and 2000-2004. We also assessed the ratio of the subpopulation of subjects under five years of age. As results, the mean age (standard deviation (SD)) at start of GH treatment was significantly different among the three groups (10.95 (3.63), 10.15 (3.39) and 8.78 (3.61), p<0.0001). The proportion of the subjects under five years of age increased significantly over time (5.11%, 7.11% and 16.85%, p<0.0001). Mean (SD) height SD scores were also significantly different (-3.41 (0.87), -3.26 (0.81) and -3.17 (0.79), p<0.0001). However, the proportions of the karyotype of 45,X were not significantly different among the three groups (p=0.25). We concluded that age and shortness at initiation of GH treatment had been improving over time. However, these favorable trends have not fully met the conditions recommended by international clinical guidelines for TS.
Endocrine Journal 09/2008; 55(6):1065-70. · 2.03 Impact Factor
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Pediatric endocrinology reviews: PER 07/2008; 5(4):912-4.
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ABSTRACT: Growth-promoting effects and safety of growth hormone (GH) treatment in prepubertal short-statured children born small for gestational age (SGA) were evaluated in a multicenter, open-label, randomized parallel-group comparison study. Patients were randomized to two dose groups; 34 and 33 patients received GH at 0.033 and 0.067 mg/kg/day for one year, respectively. The increase of the mean height velocity standard deviation score (SDS) was significantly (p <0.0001) higher in the 0.067-mg group (from -1.4 to 4.7) than that in the 0.033-mg group (-1.9 to 2.6). A significant (p <0.0001) increase in the mean height SDS was established in the 0.067-mg group; increases of -3.1 to -2.5 vs -3.1 to -2.2 in the 0.033- and 0.067-mg groups, respectively. The trial was non-eventful. Oral glucose tolerance tests indicated a mostly normal pattern of plasma glucose before and after 12-month GH treatment. The growth-promoting effect was significantly higher with GH treatment at 0.067 mg/kg/day.
Journal of pediatric endocrinology & metabolism: JPEM 05/2008; 21(5):423-31. · 0.88 Impact Factor
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Toshiaki Tanaka,
Toshio Kawabe,
Takehiko Ohzeki,
Taro Yamauchi,
Katsuhiko Tachibana,
Susumu Kanzaki,
Keiichi Hanaki, Susumu Yokoya,
Shozo Takai,
Akihiko Kinugasa,
Shigetaka Sugihara
Pediatric endocrinology reviews: PER 04/2008; 5(3):804-9.
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Pediatric endocrinology reviews: PER 07/2007; 4(4):362-5.
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ABSTRACT: To determine the present condition of treatment of childhood-onset Graves' disease in Japan, a nationwide questionnaire survey was conducted among councilors of the Japanese Society for Pediatric Endocrinology and the Japan Thyroid Association.
Responses were received from 125 individuals, and the rate of collection of questionnaires was 47%. Methimazole was selected for first-line initial antithyroid drug therapy by 92% of respondents. Antithyroid drugs tended to be given at larger initial doses and over longer periods of time to childhood-onset patients than to adult patients, and these tendencies were more pronounced for pediatric endocrinologists. Combination therapy with an antithyroid drug and thyroxine was used more frequently by pediatric endocrinologists. Thyroidologists had more experience with radioiodine therapy than pediatric endocrinologists. Opinions regarding preparation of guidelines for the initial dose of methimazole in childhood-onset Graves' disease were almost equally divided among the following: the dose of methimazole should be adjusted according to the severity of disease as in adult cases, methimazole should be started at a dose of 1mg/kg per day in all patients, and the dose should be determined based on results of a randomized study.
The present condition of treatment of childhood-onset Graves' disease in Japan was clarified.
Thyroid 02/2007; 17(1):67-72. · 4.79 Impact Factor
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ABSTRACT: Congenital generalized lipodystrophy (CGL) is a disease characterized by generalized lack of body fat, insulin resistance, hypertriglyceridemia, and fatty liver. We studied the long-term effects of recombinant human insulin-like growth factor I (rhIGF-I) treatment on glucose and lipid metabolism and the growth in a patient with CGL. During rhIGF-I treatment, the serum triglyceride level was maintained almost within the normal range, and the plasma glycosylated hemoglobin A1c (HbA1c) levels were maintained under 8.0% (5.8%-7.9%). Thus, rhIGF-I treatment was effective in lowering glucose and triglyceride levels over the long-term in a CGL patient. However, it was difficult to suppress the patient's voracious appetite. Although serum total IGF-I levels were extremely high (1000-1700 ng/ml), growth was not accelerated after the start of rhIGF-I treatment, likely because of normal IGF binding protein 3 (IGFBP-3) levels. During rhIGF-I treatment, the patient developed a recurrence of mild hypertrophic cardiomyopathy and a mild elevation of intraocular pressure.
Endocrine Journal 11/2006; 53(5):639-45. · 2.03 Impact Factor
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ABSTRACT: We studied the effect of gonadal suppression treatment in combination with anabolic steroid on pubertal height gain and adult height in two children who entered puberty with short stature. Patient 1 was a female with idiopathic short stature. She received combined treatment with an anabolic steroid (stanozolol) and a gonadotropin releasing hormone analog (leuprorelin acetate). Her pubertal height gain was 28.5 cm, which is greater than that in normal height girls (20-25 cm). Patient 2 was a male with Aarskog syndrome. Although his growth hormone (GH) secretion was normal, he received GH treatment. Since GH administration did not accelerate his growth, he received combined treatment with stanozolol and leuprorelin acetate. His pubertal height gain was 27.0 cm, which is greater than that observed in GH deficient boys treated with GH alone (21.9 cm). Combined treatment with stanozolol and leuprorelin acetate appears to be effective in increasing pubertal height gain and adult height in children who enter puberty with short stature.
Journal of pediatric endocrinology & metabolism: JPEM 10/2006; 19(9):1125-31. · 0.88 Impact Factor
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Kunihiko Hanew,
Katsuhiko Tachibana, Susumu Yokoya,
Kenji Fujieda,
Toshiaki Tanaka,
Yutaka Igarashi,
Akira Shimatsu,
Hiroyuki Tanaka,
Takakuni Tanizawa,
Akira Teramoto,
Yoshikazu Nishi,
Yukihiro Hasegawa,
Naomi Hizuka,
Takeki Hirano,
Keinosuke Fujita
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ABSTRACT: In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 micro/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.
Endocrine Journal 05/2006; 53(2):259-65. · 2.03 Impact Factor
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The American Journal of Human Genetics 02/2006; 78(1):167-70. · 10.60 Impact Factor
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ABSTRACT: The Growth Hormone (GH) and Its Related Factors Study Committee of the Foundation for Growth Science, Japan, has been conducting a quality control study for 15 years to improve the equality of diagnosis of GH deficiency. It found that the greatest differences in measured GH values were due to the different potencies of the kit standards, which were primarily adjusted to WHO standards for human GH of pituitary origin. With the collaboration of kit makers and the Study Group of Hypothalamo-Pituitary Disorders of the Ministry of Health, Labor and Welfare, all GH kits in Japan have begun using the same recombinant human GH standard since April 2005. As a result the diagnostic cut-off peak GH has changed from 10 to 6 ng/ml.
Hormone Research 02/2005; 64 Suppl 2:6-11. · 2.48 Impact Factor
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Kunihiko Hanew,
Katsuhiko Tachibana, Susumu Yokoya,
Kenji Fujieda,
Toshiaki Tanaka,
Yutaka Igarashi,
Akira Shimatsu,
Hiroyuki Tanaka,
Takakuni Tanizawa,
Akira Teramoto,
Yoshikazu Nishi,
Yukihiro Hasegawa,
Naomi Hizuka,
Takeki Hirano,
Keinosuke Fujita
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ABSTRACT: The ratio, clinical characteristics, and therapeutic efficacy of hGH treatment in patients with severe short stature (HtSDS below -4SD) with severe GHD (all peak GH values to provocation tests: below 2 mug/L) were studied. From March 1986 to January 1998, 23,110 patients with idiopathic GH deficiency (IGHD) were registered with the Foundation for Growth Science, Japan. These subjects were divided into 5 groups as follows: Group 1 (G1), all subjects; Group 2 (G2), at least one GH peak to provocative test > or = 5 microg/L; Group 3 (G3), 2 microg/L < or = GH peak<5 microg/L; Group 4 (G4), all GH peaks<2 microg/L and HtSDS>-4; Group 5 (G5), all GH peaks<2 microg/L and HtSDS< or = -4. The ratio of G5 was 139 patients (0.6%) out of 23,110 patients with IGHD. In G5, there were no significant differences in birth weight, birth length, gestational age and parental height between G2, G3 and G4. However, asphyxia at delivery was more frequent in G5 and G4 than G2 and G3. Chronological age (CA), bone age (BA) and BA/CA ratio at registration were significantly lower in G5 than G2, G3 and G4. Further, the IGF-I SD score in G5 was significantly lower than those in G2 and G3. After hGH treatment, the final height and final height SDS in G5 remained the lowest, while the DeltaHtSDS value in G5 was the greatest among G2 to G5 groups. In conclusion, the ratio of severe short stature with severe GH deficiency (G5) is only 0.6% of all IGHD cases. Growth failure in G5 seems to occur after birth, and its etiology in G5 seems to be different from that of patients with other forms of IGHD. Early diagnosis and hGH treatment are needed to attain better final height.
Endocrine Journal 02/2005; 52(1):37-43. · 2.03 Impact Factor
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ABSTRACT: We report the usefulness of a highly sensitive immune complex transfer enzyme immunoassay (ICT-EIA) to detect human chorionic gonadotropin (HCG)-beta and thereby the onset of neurohypophyseal germinoma in its active phase. A 14-year-old girl exhibiting arrested puberty was diagnosed with neurohypophyseal germinoma following observation for two years. This patient initially showed no signs of diabetes insipidus (DI). While ICT-EIA indicated concentrations of HCG-beta higher than normal in cerebrospinal fluid (CSF) and serum, the results obtained with conventional methods were negative. ICT-EIA was also useful to assess the efficacy of treatment.
Pituitary 02/2004; 7(3):165-9. · 1.83 Impact Factor
