今日の臨床サポート

Turner症候群(小児科)

著者: 長谷川行洋 東京都立小児総合医療センター 内分泌代謝科

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:2019/09/06
患者向け説明資料

概要・推奨   

  1. 低身長の患者にはGH治療をすることが勧められる(推奨度1)。
  1. 腺機能低下症を示す患者には、女性ホルモン補充が勧められる(推奨度1)。
  1. 上行大動脈直径が20 mm/sqm以上の場合、経過観察を要する。25以上になった場合は循環器科医師にコンサルトする(推奨度1)。
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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:
長谷川行洋 : 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、薬剤と参考文献について加筆した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ターナー(Turner)症候群は、低身長、思春期発達の遅れから診断されることが多いX染色体あるいはその短腕の欠失などを特徴とする染色体異常の1つで、女性2,000人に1人以上の頻度である。
  1. 年齢ごとに疑われる徴候は異なり、新生児・乳児では身長・体重増加不良に加え、手足の浮腫(リンパ管浮腫)、翼状頚、心雑音(大動脈縮窄症に代表される心疾患)がきっかけとなり診断が疑われる。
 
手背の浮腫

左の手背にリンパ管浮腫がみられる

出典

img1:  著者提供
 
 
 
  1. 幼児期、学童期(思春期年齢前)では、低身長がきっかけとなり診断が疑われる。
  1. 思春期年齢では、思春期が発来しない、あるいは進行しないこと(原発性性腺機能低下症の合併)がきっかけとなり診断が疑われる。
  1. 低身長に対しては成長ホルモンの治療が有効であることは確立している。無治療と比べて+5~8cm程度の最終身長改善が期待できる。性腺機能低下症に関しては女性ホルモン補充が行われる。
  1. 生命予後に関する事項として、大動脈拡張、大動脈解離の合併が知られている。10歳代からの合併が知られ、20歳代以上での死亡例が知られている。
問診・診察のポイント  
  1. 年齢ごとに診断のきっかけになる徴候、症状がおよそ分かれるので、そのことを頭に入れて問診、診察を行う。低身長以外にほとんど何も診察での陽性所見がみられない本症患児が存在するため、−2SD以下の低身長女児では一度は染色体検査により本症を除外する。
  1. 新生児、乳児早期のリンパ管浮腫、翼状頚はともに他の染色体異常症(ダウン症など)でもみられ得る徴候である。

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文献 

著者: Yukihiro Hasegawa, Daisuke Ariyasu, Masako Izawa, Junko Igaki-Miyamoto, Mami Fukuma, Megumi Hatano, Hiroko Yagi, Masahiro Goto
雑誌名: Endocr J. 2017 Feb 27;64(2):221-227. doi: 10.1507/endocrj.EJ16-0170. Epub 2016 Dec 2.
Abstract/Text Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8-13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week ∼0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 ± 3.4 cm and the standard deviation (SD) was 2.02 ± 0.62 for Turner syndrome. The final height in group L was 148.5 ± 3.0 cm with a SD of 1.30 ± 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 ± 0.026 g/cm3) was significantly different from that of group L or E (0.262 or 0.262 g/cm3 as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.

PMID 27916781  Endocr J. 2017 Feb 27;64(2):221-227. doi: 10.1507/endoc・・・
著者: Claus H Gravholt, Niels H Andersen, Gerard S Conway, Olaf M Dekkers, Mitchell E Geffner, Karen O Klein, Angela E Lin, Nelly Mauras, Charmian A Quigley, Karen Rubin, David E Sandberg, Theo C J Sas, Michael Silberbach, Viveca Söderström-Anttila, Kirstine Stochholm, Janielle A van Alfen-van derVelden, Joachim Woelfle, Philippe F Backeljauw, International Turner Syndrome Consensus Group
雑誌名: Eur J Endocrinol. 2017 Sep;177(3):G1-G70. doi: 10.1530/EJE-17-0430.
Abstract/Text Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

© 2017 European Society of Endocrinology.
PMID 28705803  Eur J Endocrinol. 2017 Sep;177(3):G1-G70. doi: 10.1530/・・・
著者: David K Stephure, Canadian Growth Hormone Advisory Committee
雑誌名: J Clin Endocrinol Metab. 2005 Jun;90(6):3360-6. doi: 10.1210/jc.2004-2187. Epub 2005 Mar 22.
Abstract/Text BACKGROUND: A randomized, controlled trial of GH supplementation to adult height in girls with short stature due to Turner syndrome was conducted in Canada. We report results in subjects who completed the protocol and subjects who participated in follow-up.
METHODS: One hundred fifty-four girls with Turner syndrome, aged 7-13 yr, were randomly assigned to one of two groups: 1) GH by sc injection six times per week (0.30 mg/kg.wk), and 2) control (C), no GH treatment. Both cohorts received standardized sex steroid replacement starting at a chronological age of 13 yr. Subjects were followed until protocol completion, defined as height velocity less than 2 cm/yr and bone age 14 yr or greater. A subsequent protocol addendum requested follow-up safety and efficacy assessment in all patients at least 1 yr after the last core protocol visit.
RESULTS: One hundred four patients completed the study (61 GH, 43 C), and 50 withdrew (15 GH, 35 C). At protocol completion, mean heights were 147.5 +/- 6.1 (GH) and 141.0 +/- 5.4 cm (C), respectively (P < 0.001). Of those who completed the protocol, 59 (40 GH, 19 C) had height data at least 1 yr after protocol completion; in that group, mean heights were 149.0 +/- 6.4 (GH) and 142.2 +/- 6.6 cm (C), respectively (P < 0.001). At protocol completion and follow-up, the mean height gain due to GH, estimated by analysis of covariance, was +7.2 cm (confidence interval 6.0, 8.4) and +7.3 cm (confidence interval 5.4, 9.2), respectively (both P < 0.001).
CONCLUSIONS: This is the first evidence from a randomized, controlled trial to adult height that GH supplementation with induction of puberty at a near physiological age increases the adult height of girls with Turner syndrome.

PMID 15784709  J Clin Endocrinol Metab. 2005 Jun;90(6):3360-6. doi: 10・・・
著者: Carolyn A Bondy, Turner Syndrome Study Group
雑誌名: J Clin Endocrinol Metab. 2007 Jan;92(1):10-25. doi: 10.1210/jc.2006-1374. Epub 2006 Oct 17.
Abstract/Text OBJECTIVES: The objective of this work is to provide updated guidelines for the evaluation and treatment of girls and women with Turner syndrome (TS).
PARTICIPANTS: The Turner Syndrome Consensus Study Group is a multidisciplinary panel of experts with relevant clinical and research experience with TS that met in Bethesda, Maryland, April 2006. The meeting was supported by the National Institute of Child Health and unrestricted educational grants from pharmaceutical companies.
EVIDENCE: The study group used peer-reviewed published information to form its principal recommendations. Expert opinion was used where good evidence was lacking.
CONSENSUS: The study group met for 3 d to discuss key issues. Breakout groups focused on genetic, cardiological, auxological, psychological, gynecological, and general medical concerns and drafted recommendations for presentation to the whole group. Draft reports were available for additional comment on the meeting web site. Synthesis of the section reports and final revisions were reviewed by e-mail and approved by whole-group consensus.
CONCLUSIONS: We suggest that parents receiving a prenatal diagnosis of TS be advised of the broad phenotypic spectrum and the good quality of life observed in TS in recent years. We recommend that magnetic resonance angiography be used in addition to echocardiography to evaluate the cardiovascular system and suggest that patients with defined cardiovascular defects be cautioned in regard to pregnancy and certain types of exercise. We recommend that puberty should not be delayed to promote statural growth. We suggest a comprehensive educational evaluation in early childhood to identify potential attention-deficit or nonverbal learning disorders. We suggest that caregivers address the prospect of premature ovarian failure in an open and sensitive manner and emphasize the critical importance of estrogen treatment for feminization and for bone health during the adult years. All individuals with TS require continued monitoring of hearing and thyroid function throughout the lifespan. We suggest that adults with TS be monitored for aortic enlargement, hypertension, diabetes, and dyslipidemia.

PMID 17047017  J Clin Endocrinol Metab. 2007 Jan;92(1):10-25. doi: 10.・・・
著者: Marsha L Davenport
雑誌名: J Clin Endocrinol Metab. 2010 Apr;95(4):1487-95. doi: 10.1210/jc.2009-0926.
Abstract/Text Turner syndrome (TS) occurs in about 1:4000 live births and describes females with a broad constellation of problems associated with loss of an entire sex chromosome or a portion of the X chromosome containing the tip of its short arm. TS is associated with an astounding array of potential abnormalities, most of them thought to be caused by haploinsufficiency of genes that are normally expressed by both X chromosomes. A health care checklist is provided that suggests screening tests at specific ages and intervals for problems such as strabismus, hearing loss, and autoimmune thyroid disease. Four areas of major concern in TS are discussed: growth failure, cardiovascular disease, gonadal failure, and learning disabilities. GH therapy should generally begin as soon as growth failure occurs, allowing for rapid normalization of height. Cardiac imaging, preferably magnetic resonance imaging, should be performed at diagnosis and repeated at 5- to 10-yr intervals to assess for congenital heart abnormalities and the emergence of aortic dilatation, a precursor to aortic dissection. Hypertension should be aggressively treated. For those with gonadal dysgenesis, hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 yr. Transdermal estradiol provides the most physiological replacement. Finally, nonverbal learning disabilities marked by deficits in visual-spatial-organizational skills, complex psychomotor skills, and social skills are common in TS. Neuropsychological testing should be routine and families given support in obtaining appropriate therapy, including special accommodations at school.

PMID 20375216  J Clin Endocrinol Metab. 2010 Apr;95(4):1487-95. doi: 1・・・
著者: Carolyn A Bondy
雑誌名: Congenit Heart Dis. 2008 Jan-Feb;3(1):2-15. doi: 10.1111/j.1747-0803.2007.00163.x.
Abstract/Text Turner syndrome (TS), or monosomy X, occurs in approximately 1/2000 live born females. Intelligence is normal and short stature is the most obvious and consistent feature of the syndrome. Congenital cardiovascular disease affects approximately 50% of individuals and is the major cause of premature mortality in adults. Unfortunately, this most important aspect of the syndrome has received little attention outside of pediatric medicine, and adult cardiological follow-up is seriously lacking. This review describes the spectrum of cardiovascular defects with particular attention to identifying risk factors for aortic dissection/rupture. X-chromosome genetic pathways implicated in Turner cardiovascular disease, including premature coronary artery disease, are discussed. Recent guidelines for diagnosis and treatment of girls and women with TS are reviewed.

PMID 18373744  Congenit Heart Dis. 2008 Jan-Feb;3(1):2-15. doi: 10.111・・・
著者: Bianca Bianco, Mônica Lipay, Alexis Guedes, Kelly Oliveira, Ieda T N Verreschi
雑誌名: Int J Gynecol Pathol. 2009 Mar;28(2):197-202. doi: 10.1097/PGP.0b013e318186a825.
Abstract/Text The presence of Y-chromosome material in patients with dysgenetic gonads increases the risk of gonadal tumors and/or nontumoral androgen-producing lesions. The patients' prognosis can vary, depending on their karyotype. The objective of this study was to investigate the presence of Y-chromosome mosaicism in Turner syndrome patients and its association with the development of gonadal tumors and/or nontumoral androgen-producing lesions. Eighty-seven Turner syndrome patients were studied. Genomic DNA was extracted from peripheral blood and genes SRY and TSPY and DYZ3 repeat of the Y chromosome were amplified by polymerase chain reaction. To the Y-positive patients, prophylactic gonadectomy was offered. The data disclosed hidden Y-chromosome mosaicism in 16 (18.5%) of the patients. SRY sequence was detected in all of the 16 patients, and 4 (4.6%) of them presented DYZ3 repeat region and TSPY gene. Eleven of the patients with Y-positive sequences agreed to undergo the prophylactic surgery. In 2 cases, bilateral gonadoblastoma was found and, in another case, the histopathologic study of the gonads revealed hilus cell hyperplasia. In a further case, there were hilus cell hyperplasia and a stromal luteoma. In conclusion, a systematic search for hidden Y-chromosome mosaicism, especially SRY, in Turner syndrome patients is justified by the possibility of preventing gonadal lesions.

PMID 19188812  Int J Gynecol Pathol. 2009 Mar;28(2):197-202. doi: 10.1・・・
著者: Bianca Bianco, Mônica Vannucci Nunes Lipay, Maria Isabel Melaragno, Alexis Dourado Guedes, Ieda T N Verreschi
雑誌名: J Pediatr Endocrinol Metab. 2006 Sep;19(9):1113-7.
Abstract/Text UNLABELLED: The presence of Y chromosome fragments in patients with Turner's syndrome (TS) is known to increase the risk of gonadoblastoma. The investigation of Y sequences is usually performed only in the presence of marker chromosomes and therefore does not rule out the presence of hidden mosaicism in patients with 45,X TS without any marker.
AIMS: 1. To investigate the presence of hidden Y mosaicism in non-mosaic 45,X patients with TS, using samples from different tissues, and its association with the development of gonadoblastoma.
STUDY DESIGN: Twenty patients with a 45,X karyotype were studied. The SRY and DYZ3 sequences were amplified by PCR, using genomic DNA from peripheral blood, oral epithelial cells and hair roots. Prophylactic gonadectomy was offered to the Y-positive patients.
RESULTS: The analysis of the different tissues revealed that seven (35%) out of the 20 patients studied presented hidden chromosome Y mosaicism. Four of these patients underwent prophylactic gonadectomy, and bilateral gonadoblastoma was found in one of them.
CONCLUSIONS: A systematic search for hidden Y chromosome mosaicism in patients with TS and 45,X karyotype is justified by the possibility of developing gonadoblastoma.

PMID 17128558  J Pediatr Endocrinol Metab. 2006 Sep;19(9):1113-7.
著者: A Sallai, J Sólyom, M Dobos, J Szabó, Z Halász, L Ságodi, T Niederland, A Kozári, R Bertalan, P Ugocsai, G Fekete
雑誌名: J Endocrinol Invest. 2010 Apr;33(4):222-7. doi: 10.1007/BF03345783. Epub 2009 Jul 21.
Abstract/Text BACKGROUND: The presence of Y-chromosome material in patients with Turner syndrome (TS) is a risk factor for the development of gonadoblastoma. Cytogenetic analysis detects Y-chromosome mosaicism in about 5% of Turner patients. However, if Y-chromosome sequences are present in only a few cells, they may be missed by routine analysis. The use of molecular techniques to detect the presence of Y-chromosome fragments in such patients is becoming increasingly important.
AIM: The objective of our study was to analyze cryptic Y-chromosome derivatives in Hungarian TS patient population by real-time PCR (RT-PCR).
SUBJECTS AND METHODS: Cytogenetic and RT-PCR methods were used to examine peripheral blood DNA of 130 Hungarian patients with TS for the presence of Y-chromosome. With RT-PCR, 4 regions throughout the Y-chromosome were analyzed.
RESULTS: Initial cytogenetic karyotyping assessing 10-50 metaphases revealed 3 patients with Y-chromosome positivity. RT-PCR revealed further 6 patients with Y-chromosome, who were initially considered as Y-negatives by standard kayotyping. The consecutive cytogenetic analysis of a large number (about 100) of metaphases (in 5 patients) and/or FISH (in 6 patients) however, also confirmed the presence of the Y-chromosome in these patients. Prophylactic gonadectomy was carried out in all 9 patients and 1 of them was diagnosed as having bilateral gonadoblastoma without clinical symptoms.
CONCLUSIONS: We recommend a routine molecular screening for hidden Y-chromosome sequences in Turner patients, who are negative for Y-chromosome by conventional cytogenetic analysis, in order to calculate the future risk of developing gonadoblastoma.

PMID 19625757  J Endocrinol Invest. 2010 Apr;33(4):222-7. doi: 10.1007・・・

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