今日の臨床サポート

成長障害(小児科)

著者: 田中裕之 東京大学大学院医学系研究科 生殖・発達・加齢医学専攻 小児医学講座

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2019/08/19
患者向け説明資料

概要・推奨   

  1. 治療は原疾患に基づいて行われる(推奨度1)。
  1. Prader-Willi症候群の患者では乳児期からのGH療法が推奨される(推奨度1)。
  1. 軟骨無形成症の患者の最終身長に対するGH療法は一定の効果が得られる(推奨度3)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
田中裕之 : 特に申告事項無し[2021年]
監修:五十嵐隆 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、Noonan症候群について加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 同性、同年齢の標準身長の-2.0 SD以下の身長であるとき、または成長速度が2年以上にわたって標準値の-1.5 SD以下である場合を成長障害と定義する。
  1. 身長は両親の遺伝的影響を受けるため目標身長を算出し、男児では目標身長の±9cm、女児では±8cmを下回る場合は何らかの疾患の存在を考慮する。
 
目標身長

目標身長は、児の最終身長が両親の身長の影響を受けること、平均身長の男女差が約13cmであることから、上記のように計算する。

出典

img1:  後藤正博先生ご提供
 
 
 
  1. 低身長(成長障害)の原因としては特発性低身長、家族性低身長、思春期遅発症などの病的意義のない低身長を来す疾患が60~80%を占める。
  1. 乳幼児期は栄養摂取により身長・体重の推移が大きく影響されるため基礎疾患の有無を鑑別するうえで注意を要する。
 
低身長小児の原因分類

2002年3月~2005年6月に国立成育医療研究センターで受診した患者。

 
問診・診察のポイント  
 
  1. 出生歴では在胎週数、出生時体重、体長を記録し、在胎週別の標準値と比較して子宮内発育遅延の有無を調べる。成長ホルモン分泌不全性低身長を呈する下垂体機能低下症の危険因子である骨盤位分娩、新生児仮死、黄疸の有無もチェックする。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: W P Robinson, A Bottani, Y G Xie, J Balakrishman, F Binkert, M Mächler, A Prader, A Schinzel
雑誌名: Am J Hum Genet. 1991 Dec;49(6):1219-34.
Abstract/Text Thirty-seven patients presenting features of the Prader-Willi syndrome (PWS) have been examined using cytogenetic and molecular techniques. Clinical evaluation showed that 29 of these patients fulfilled diagnostic criteria for PWS. A deletion of the 15q11.2-q12 region could be identified molecularly in 21 of these cases, including several cases where the cytogenetics results were inconclusive. One clinically typical patient is deleted at only two of five loci normally included in a PWS deletion. A patient carrying a de novo 13;X translocation was not deleted for the molecular markers tested but was clinically considered to be "atypical" PWS. In addition, five cases of maternal heterodisomy and two of isodisomy for 15q11-q13 were observed. All of the eight patients who did not fulfill clinical diagnosis of PWS showed normal maternal and paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. A comparison of clinical features between deletion patients and disomy patients shows no significant differences between the two groups. The parental ages at birth of disomic patients were significantly higher than those for deletion patients. As all typical PWS cases showed either a deletion or disomy of 15q11.2-q12, molecular examination should provide a reliable diagnostic tool. As the disomy patients do not show either any additional or more severe features than typical deletion patients do, it is likely that there is only one imprinted region on chromosome 15 (within 15q11.2-q12).

PMID 1684085  Am J Hum Genet. 1991 Dec;49(6):1219-34.
著者: M J Mascari, W Gottlieb, P K Rogan, M G Butler, D A Waller, J A Armour, A J Jeffreys, R L Ladda, R D Nicholls
雑誌名: N Engl J Med. 1992 Jun 11;326(24):1599-607. doi: 10.1056/NEJM199206113262404.
Abstract/Text BACKGROUND: Prader-Willi syndrome is a genetic disorder characterized by infantile hypotonia, obesity, hypogonadism, and mental retardation, but it is difficult to diagnose clinically in infants and young children. In about two thirds of patients, a cytogenetically visible deletion can be detected in the paternally derived chromosome 15 (15q11q13). Recently, patients with Prader-Willi syndrome have been described who do not have the cytogenetic deletion but instead have two copies of the 15q11q13 region that are inherited from the mother (with none inherited from the father). This unusual form of inheritance is known as maternal uniparental disomy. Using molecular genetic techniques, we sought to determine the frequency of uniparental disomy in Prader-Willi syndrome.
METHODS: We performed molecular analyses using DNA markers within 15q11q13 and elsewhere on chromosome 15 in 30 patients with Prader-Willi syndrome who had no cytogenetically visible deletion. We also studied their parents. Three patients with Prader-Willi syndrome who had a cytogenetic deletion served as controls.
RESULTS: In 18 of the 30 patients without a cytogenetic deletion (60 percent), we demonstrated the presence of maternal uniparental disomy for chromosome 15 and its association with advanced maternal age. In another eight patients (27 percent), we identified large molecular deletions. The remaining four patients (13 percent) had evidence of normal biparental inheritance for chromosome 15; three of these patients were the only ones in the study who had some atypical clinical features.
CONCLUSIONS: In about 20 percent of all cases, Prader-Willi syndrome results from the inheritance of both copies of chromosome 15 from the mother (maternal uniparental disomy). With the combined use of cytogenetic and molecular techniques, the genetic basis of Prader-Willi syndrome can be identified in up to 95 percent of patients.

PMID 1584261  N Engl J Med. 1992 Jun 11;326(24):1599-607. doi: 10.105・・・
著者: Tomoko Saito, Keisuke Nagasaki, Gen Nishimura, Masaki Takagi, Tomonobu Hasegawa, Makoto Uchiyama
雑誌名: Am J Med Genet A. 2012 Mar;158A(3):630-4. doi: 10.1002/ajmg.a.34424. Epub 2012 Feb 2.
Abstract/Text Hypochondroplasia (HCH) is the mildest phenotype among fibroblast growth factor receptor 3 (FGFR3)-associated skeletal dysplasias. Affected individuals usually presents with mild short stature in preschool age. It was uncommon that a diagnosis of HCH is made in young affected children. Recently, however, prenatal ultrasound (US) has increased likelihood of detecting in utero mild short limbs. There have been a few reports on the early diagnosis of HCH in the neonatal period preceded by a suspicion of skeletal dysplasia on fetal US. However, the proper diagnosis of HCH is hampered by absence of the radiological criteria relevant to age, particularly those in the neonatal period. We report on the clinical and radiological findings in two HCH children with a FGFR3 mutation. In both children, fetal US showed short femora and relatively increased biparietal diameter (BPD). However, postnatal assessment failed to make a specific diagnosis in the neonatal period. The correct diagnosis of HCH was accomplished by reassessment after exacerbation of postnatal short stature. In retrospective radiological review, the radiological findings relevant to HCH were discernible more easily in the neonatal period than at age of 3 years.

Copyright © 2012 Wiley Periodicals, Inc.
PMID 22302603  Am J Med Genet A. 2012 Mar;158A(3):630-4. doi: 10.1002/・・・
著者: Amy E Roberts, Judith E Allanson, Marco Tartaglia, Bruce D Gelb
雑誌名: Lancet. 2013 Jan 26;381(9863):333-42. doi: 10.1016/S0140-6736(12)61023-X. Epub 2013 Jan 10.
Abstract/Text Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23312968  Lancet. 2013 Jan 26;381(9863):333-42. doi: 10.1016/S014・・・
著者: Moris A Angulo, Mariano Castro-Magana, Michele Lamerson, Raul Arguello, Siham Accacha, Asjad Khan
雑誌名: Am J Med Genet A. 2007 Jul 1;143A(13):1456-61. doi: 10.1002/ajmg.a.31824.
Abstract/Text Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.

(c) 2007 Wiley-Liss, Inc.
PMID 17567883  Am J Med Genet A. 2007 Jul 1;143A(13):1456-61. doi: 10.・・・
著者: Aaron L Carrel, Susan E Myers, Barbara Y Whitman, Jens Eickhoff, David B Allen
雑誌名: J Clin Endocrinol Metab. 2010 Mar;95(3):1131-6. doi: 10.1210/jc.2009-1389. Epub 2010 Jan 8.
Abstract/Text BACKGROUND: Children with Prader-Willi syndrome (PWS) have decreased muscle mass, hypotonia, and impaired linear growth. Recombinant human GH (hGH) treatment reportedly improves body composition and physical function in children with PWS, but these studies lack long-term control data. To assess the impact of hGH therapy begun early in life on the natural history of PWS, we compared height, body composition, and strength in similar-age children with PWS naïve to hGH with those treated with hGH for 6 yr.
OBJECTIVES: Forty-eight children with PWS were studied: 21 subjects (aged 6-9 yr) treated with hGH for 6 yr (beginning at 4-32 months, mean 13 +/- 6 months) were compared with 27 children of similar age (5-9 yr) prior to treatment with hGH. Percent body fat, lean body mass, carbohydrate/lipid metabolism, and motor strength were compared using analysis of covariance.
RESULTS: PWS children treated with hGH demonstrated lower body fat (mean, 36.1 +/- 2.1 vs. 44.6 +/- 1.8%, P < 0.01), greater height (131 +/- 2 vs. 114 +/- 2 cm; P < 0.001), greater motor strength [increased standing broad jump 22.9 +/- 2.1 vs. 14.6 +/- 1.9 in. (P < 0.001) and sit-ups 12.4 +/- 0.9 vs. 7.1 +/- 0.7 in 30 sec (P < 0.001)], increased high-density lipoprotein cholesterol (58.9 +/- 2.6 vs. 44.9 +/- 2.3 mg/dl, P < 0.001), decreased low-density lipoprotein (100 +/- 8 vs. 131 +/- 7 mg/dl, P < 0.01), and no difference in fasting glucose or insulin.
CONCLUSIONS: hGH treatment in children with PWS, begun prior to 2 yr of age, improves body composition, motor function, height, and lipid profiles. The magnitude of these effects suggests that long-term hGH therapy favorably alters the natural history of PWS to an extent that exceeds risks and justifies consideration for initiation during infancy.

PMID 20061431  J Clin Endocrinol Metab. 2010 Mar;95(3):1131-6. doi: 10・・・
著者: Niels Thomas Hertel, Ole Eklöf, Sten Ivarsson, Stefan Aronson, Otto Westphal, Ilkka Sipilä, Ilkka Kaitila, Jon Bland, Dag Veimo, Jørn Müller, Klaus Mohnike, Lo Neumeyer, Martin Ritzen, Lars Hagenäs
雑誌名: Acta Paediatr. 2005 Oct;94(10):1402-10.
Abstract/Text BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature.
AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia.
METHODS: Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y.
RESULTS: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change.
CONCLUSION: GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.

PMID 16299871  Acta Paediatr. 2005 Oct;94(10):1402-10.
著者: Noriko Tanaka, Noriyuki Katsumata, Reiko Horikawa, Toshiaki Tanaka
雑誌名: Endocr J. 2003 Feb;50(1):69-75.
Abstract/Text The effects of recombinant human growth hormone (rhGH) treatment for three years were compared in patients with achondroplasia (ACH) and hypochondroplasia (HCH), whose diagnosis had been confirmed by DNA analysis of the fibroblast growth factor receptor 3 gene. Height SDS (H-SDS) and height velocity SDS (HV-SDS) using the standard for ACH significantly improved during three-year treatment as compared with that before treatment in both ACH and HCH except HV-SDS in the third year. The improvement was much greater in HCH than in ACH. The mean increase H-SDS using the standard for ACH in three years in ACH (from -0.2 SD to 0.1 SD) is almost negligible but that in HCH (from 1.2 SD to 2.6 SD) can be estimated as effective clinically. It can be concluded short-term GH treatment in HCH is effective to increase growth rate and H-SDS, but it has little effect in ACH. Further studies would be required to confirm the other beneficial effects of GH treatment such as increase in bone mineral density in ACH and HCH and the effect on the final height.

PMID 12733711  Endocr J. 2003 Feb;50(1):69-75.
著者: Daisuke Harada, Noriyuki Namba, Yuki Hanioka, Kaoru Ueyama, Natsuko Sakamoto, Yukako Nakano, Masafumi Izui, Yuiko Nagamatsu, Hiroko Kashiwagi, Miho Yamamuro, Yoshihito Ishiura, Ayako Ogitani, Yoshiki Seino
雑誌名: Eur J Pediatr. 2017 Jul;176(7):873-879. doi: 10.1007/s00431-017-2923-y. Epub 2017 May 13.
Abstract/Text The objective of this study was to evaluate the gain in final height of achondroplasia (ACH) patients with long-term growth hormone (GH) treatment. We analyzed medical data of 22 adult patients (8 males and 14 females) treated with GH at a dose of 0.05 mg/kg/day. Optionally, tibial lengthening (TL) was performed with the Ilizalov method in 15 patients and TL as well as femoral lengthening (FL) in 6 patients. Concomitant gonadal suppression therapy with buserelin acetate was applied in 13 patients. The mean treatment periods with GH were 10.7 ± 4.0 and 9.3 ± 2.5 years for males and females, respectively. GH treatment augmented the final height +0.60 ± 0.52 SD (+3.5 cm) and +0.51 ± 1.29 SD (+2.8 cm) in males and females compared to non-treated ACH patients, respectively. Final height of ACH patients that underwent GH and TL increased +1.72 ± 0.72 SD (+10.0 cm) and +1.95 ± 1.34 SD (+9.8 cm) in males and females, respectively. GH, TL, and FL increased their final height +2.97 SD (+17.2 cm) and +3.41 ± 1.63 SD (+17.3 cm) in males and females, respectively. Gonadal suppression therapy had no impact on final height.
CONCLUSIONS: Long-term GH treatment contributes to 2.6 and 2.1% of final adult height in male and female ACH patients, respectively.

PMID 28501952  Eur J Pediatr. 2017 Jul;176(7):873-879. doi: 10.1007/s0・・・
著者: Michael B Ranke, Anders Lindberg, Martin Carlsson, Cecilia Camacho-Hübner, Raoul Rooman
雑誌名: Horm Res Paediatr. 2019;91(1):46-55. doi: 10.1159/000498859. Epub 2019 Apr 2.
Abstract/Text BACKGROUND/AIMS: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years.
PATIENTS/METHODS: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined.
RESULTS: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of -3.2 and -3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed.
CONCLUSION: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.

© 2019 S. Karger AG, Basel.
PMID 30939478  Horm Res Paediatr. 2019;91(1):46-55. doi: 10.1159/00049・・・
著者: D Haffner, F Schaefer, R Nissel, E Wühl, B Tönshoff, O Mehls
雑誌名: N Engl J Med. 2000 Sep 28;343(13):923-30. doi: 10.1056/NEJM200009283431304.
Abstract/Text BACKGROUND: Growth hormone treatment stimulates growth in short children with chronic renal failure. However, the extent to which this therapy increases final adult height is not known.
METHODS: We followed 38 initially prepubertal children with chronic renal failure treated with growth hormone for a mean of 5.3 years until they reached their final adult height. The mean (+/-SD) age at the start of treatment was 10.4+/-2.2 years, the mean bone age was 7.1+/-2.3 years, and the mean height was 3.1+/-1.2 SD below normal. Fifty matched children with chronic renal failure who were not treated with growth hormone served as controls.
RESULTS: The children treated with growth hormone had sustained catch-up growth, whereas the control children had progressive growth failure. The mean final height of the growth hormone-treated children was 165 cm for boys and 156 cm for girls. The mean final adult height of the growth hormone-treated children was 1.6+/-1.2 SD below normal, which was 1.4 SD above their standardized height at base line (P< 0.001). In contrast, the final height of the untreated children (2.1+/-1.2 SD below normal) was 0.6 SD below their standardized height at base line (P<0.001). Although prepubertal bone maturation was accelerated in growth hormone-treated children, treatment was not associated with a shortening of the pubertal growth spurt. The total height gain was positively associated with the initial target-height deficit and the duration of growth hormone therapy and was negatively associated with the percentage of the observation period spent receiving dialysis treatment.
CONCLUSIONS: Long-term growth hormone treatment of children with chronic renal failure induces persistent catch-up growth, and the majority of patients achieve normal adult height.

PMID 11006368  N Engl J Med. 2000 Sep 28;343(13):923-30. doi: 10.1056/・・・
著者: Richard Nissel, Anders Lindberg, Otto Mehls, Dieter Haffner, Pfizer International Growth Database (KIGS) International Board
雑誌名: J Clin Endocrinol Metab. 2008 Apr;93(4):1359-65. doi: 10.1210/jc.2007-2302. Epub 2008 Jan 15.
Abstract/Text CONTEXT: GH therapy is an accepted measure to increase adult height in young prepubertal patients suffering from growth failure related to chronic kidney disease (CKD). The impact of GH therapy on final height (FH) in CKD patients of pubertal age is unclear.
OBJECTIVE: This study set out to analyze near-FH in a cohort of GH-treated CKD patients.
DESIGN, SETTINGS, AND PATIENTS: Of 240 evaluable patients in the Pfizer International Growth Database (KIGS) with CKD, 39% were prepubertal and 61% were pubertal at baseline; 45% were on conservative treatment for CKD, 28% were on dialysis, and 27% were in the period after renal transplantation.
MAIN OUTCOME MEASURES: Near-FH, relation to pubertal stage, and factors predictive of growth response were the main outcome measures.
RESULTS: Mean height sd scores increased continuously during GH treatment until near-FH by 1.2 and 1.6 in boys and girls, respectively. Mean near-FH differed significantly from prepubertal patients showing severely delayed puberty (-3.6), late pubertal patients (-2.9), early pubertal patients (-2.2), and prepubertal patients with normal onset of puberty (-2.0). The initial degree of stunting, degree of bone age retardation, duration of GH therapy, time spent on conservative treatment/dialysis, pubertal delay (>2 sd), gender, and age at start of GH treatment were significant predictors of growth response to GH therapy, explaining between 33 and 61% of the overall variability.
CONCLUSIONS: Long-term GH therapy of CKD patients in prepubertal and pubertal age results in an increased adult height, but response is diminished in patients on dialysis and/or with severely delayed puberty.

PMID 18198222  J Clin Endocrinol Metab. 2008 Apr;93(4):1359-65. doi: 1・・・
著者: Yvonne Van Pareren, Paul Mulder, Mieke Houdijk, Maarten Jansen, Maarten Reeser, Anita Hokken-Koelega
雑誌名: J Clin Endocrinol Metab. 2003 Aug;88(8):3584-90. doi: 10.1210/jc.2002-021172.
Abstract/Text The GH dose-response effect of long-term continuous GH treatment on adult height (AH) was evaluated in 54 short children born small for gestational age (SGA) who were participating in a randomized, double-blind, dose-response trial. Patients were randomly and blindly assigned to treatment with either 3 IU (group A) or 6 IU (group B) GH/m(2).d ( approximately 0.033 or 0.067 mg/kg.d, respectively). The mean (+/-SD) birth length was -3.6 (1.4), the age at the start of the study was 8.1 (1.9) yr, and the height SD score (SDS) at the start of the study -3.0 (0.7). Seventeen of the 54 children were partially GH deficient (stimulated GH peak, 10-20 mU/liter). Fifteen non-GH-treated, non-GH-deficient, short children born SGA, with similar inclusion criteria, served as controls [mean (+/-SD) birth length, -3.3 (1.2); age at start, 7.8 (1.7) yr; height SDS at start, -2.6 (0.5)]. GH treatment resulted in an AH above -2 SDS in 85% of the children after a mean (+/-SD) GH treatment period of 7.8 (1.7) yr. The mean (SD) AH SDS was -1.1 (0.7) for group A and -0.9 (0.8) for group B, resulting from a mean (+/-SD) gain in height SDS of 1.8 (0.7) for group A and 2.1 (0.8) for group B. No significant differences between groups A and B were found for AH SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.2, 0.6; P > 0.2) and gain in height SDS (mean difference, 0.3 SDS; 95% confidence interval, -0.1, 0.7; P > 0.1). When corrected for target height, the mean corrected AH SDS was -0.2 (0.8) for group A and -0.4 (0.9) for group B. The mean (+/-SD) AH SDS of the control group [-2.3 (0.7)] was significantly lower than that of the GH-treated group (P < 0.001). Multiple regression analysis indicated the following predictive variables for AH SDS: target height SDS, height SDS, and chronological age minus bone age (years) at the start of the study. GH dose had no significant effect. In conclusion, long-term continuous GH treatment in short children born SGA without signs of persistent catch-up growth leads to a normalization of AH, even with a GH dose of 3 IU/m(2).d ( approximately 0.033 mg/kg.d).

PMID 12915640  J Clin Endocrinol Metab. 2003 Aug;88(8):3584-90. doi: 1・・・
著者: Susumu Yokoya, Toshiaki Tanaka, Kazuo Itabashi, Hisao Osada, Hideaki Hirai, Yoshiki Seino
雑誌名: Clin Pediatr Endocrinol. 2018;27(4):225-234. doi: 10.1297/cpe.27.225. Epub 2018 Oct 30.
Abstract/Text The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in Japanese children with small-for-gestational-age short stature. A total of 88 patients were enrolled in the comparative and extension studies. At the end of the comparative study (24 mo), the mean height SD score for chronological age had significantly increased in the 0.23 mg/kg/wk and 0.47 mg/kg/wk groups with increments of 0.84 ± 0.42 and 1.50 ± 0.44 SD, respectively. In the extension study, the dose could be increased based on the pre-defined growth criteria. Increments in height SD scores over the 24 to 36 mo period at doses of 0.23 mg/kg/wk, 0.23 to 0.47 mg/kg/wk, and 0.47 mg/kg/wk were 0.25 ± 0.28, 0.46 ± 0.21, and 0.28 ± 0.16 SD, respectively. The growth effect increased following dose escalation even in the low responders in the initial 2-yr treatment at 0.23 mg/kg/wk, indicating the effectiveness of dose escalation in accordance with the Japanese guidelines. rhGH at 0.47 mg/kg/wk provided a greater degree of growth promotion after 24 mo. The safety profile appeared to be tolerable and was similar in all groups. Considering the increased insulin resistance, the recommendations of the regulatory authorities should be followed to minimize the risks of rhGH treatment.

PMID 30393439  Clin Pediatr Endocrinol. 2018;27(4):225-234. doi: 10.12・・・
著者: M V Mericq, M Eggers, A Avila, G B Cutler, F Cassorla
雑誌名: J Clin Endocrinol Metab. 2000 Feb;85(2):569-73. doi: 10.1210/jcem.85.2.6343.
Abstract/Text To study the effects of delaying puberty in GH-deficient (GHD) children, we studied 21 GHD (9 boys, 14 girls), treatment-naive, pubertal patients in a prospective, randomized trial. Their chronological age was 14.3 +/- 1.6 yr, and their bone age was 11.3 +/- 1.1 yr (mean +/- SD) at the beginning of the study. Four patients who developed hypogonadotropic hypogonadism were subsequently excluded from the study. Patients were randomly assigned to receive GH + LH-releasing hormone analog (LHRH-A) (n = 7), or GH alone (n = 10). GH and LHRH-A treatment started simultaneously in each patient. GH (Nutropin) was administered at a dose of 0.1 U/kg x day sc, until patients reached a bone age (BA) of 14 yr in girls and 16 yr in boys, and LHRH-A (Lupron depot) was administered at a dose of 300 microg/ kg every 28 days in during 3 yr. We defined GH deficiency as patients with a growth velocity less than 4 cm/yr, BA delay more than 1 yr in relationship to chronological age, GH response to two stimulation tests less than 7 microg/L, associated with low serum insulin-like growth factor I and insulin-like growth factor binding protein 3 levels. Statistical analysis was performed by ANOVA or Kruskall Wallis when variances were not homogeneous. We observed a significant decrease in the rate of BA maturation in the group treated with GH+LHRH-A (1.5 +/- 0.2 yr) compared with the group treated with GH alone (4.2 +/-0.5 yr) during the 3 years of LHRH-A therapy (P < 0.05). This delay in BA maturation produced a significant gain in final height in the group treated with GH+LHRH-A, which reached - 1.3 +/- 0.5 SD score compared with -2.7 +/- 0.3 SD score (P < 0.05) in the group treated with GH alone. These results indicate that delaying puberty with LHRH-A in GHD children during treatment with GH increases final height.

PMID 10690857  J Clin Endocrinol Metab. 2000 Feb;85(2):569-73. doi: 10・・・
著者: Verónica Mericq, Héctor Gajardo, Martha Eggers, Alejandra Avila, Fernando Cassorla
雑誌名: J Clin Endocrinol Metab. 2002 Jan;87(1):84-9. doi: 10.1210/jcem.87.1.8148.
Abstract/Text The aim of the present study was to assess the impact of treatment with GH with or without LHRH analog (LHRH-A) on bone mineralization of GH-deficient adolescents. We studied 17 pubertal, treatment-naive, GH-deficient patients (10 girls and 7 boys) in a prospective, randomized trial. Mean chronological age and mean bone age were 14.1 +/- 0.4 and 11.3 +/- 0.3 yr, respectively, at the beginning of the study. Treatment with GH + LHRH-A (n = 7) or GH alone (n = 10) started simultaneously. Nutropin was administered at a dose of 0.1 U/kg per day sc until patients reached near final height (NFH), defined as a bone age of 14 yr in girls and 16 yr in boys. Mean time of GH therapy in the patients treated with GH+LHRH-A was 4.8 +/- 0.5 yr and in the patients treated with GH alone 2.9 +/- 0.7 yr. Lupron was administered at a dose of 300 microg/kg every 28 d im for 3 yr. Bone mineral density (BMD) was assessed yearly by dual-energy x-ray absorptiometry at the lumbar spine (L2-L4) and femoral neck at the beginning of the study, after 3 yr of hormonal therapy, and at NFH. Statistical analysis was performed by t test and ANOVA. We observed a significant increase in lumbar and femoral bone mineral content, BMD, SD score, and bone mineral apparent density, compared with baseline in both groups of patients, regardless of whether they were treated with GH alone or in combination with LHRH-A. The patients treated with GH + LHRH-A had a significantly lower bone mineral content after 3 yr of therapy. This difference, however, did not persist after both groups of patients reached NFH. These results indicate that delaying puberty with LHRH-A in GH-deficient patients treated with GH diminishes transient bone mineralization but does not appear to have a permanent impact on BMD.

PMID 11788628  J Clin Endocrinol Metab. 2002 Jan;87(1):84-9. doi: 10.1・・・
著者: T Tanaka, K Komatsu, G Takada, M Miyashita, T Ohno
雑誌名: Endocr J. 1998 Apr;45 Suppl:S145-9.
Abstract/Text 13,707 longitudinal records of individuals (6,749 boys and 6,958 girls) from 6 years to 17 years were fitted by means of a smoothing cubic spline function and the factors influencing the change in height SDS during puberty were analysed. Children are divided into subgroups with 0.2 SD intervals according to height SDS at 6 years. Shorter children in subgroups at 6 years tend to increase their final height SDS by entering puberty later and making their height at onset of pubertal growth spurt (PGS) relatively taller. On the other hand taller children in subgroups at 6 years tend to decrease their final height SDS by entering puberty early and make height at PGS relatively shorter. The percentage distribution of a final height SDS against subgroups at 6 years also shows this tendency. This figure is useful in predicting the probability of final height SDS in the clinical field of growth disorders.

PMID 9790251  Endocr J. 1998 Apr;45 Suppl:S145-9.

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