今日の臨床サポート

性分化疾患(小児科・産婦人科)

著者: 深見真紀 国立成育医療研究所センター 分子内分泌研究部

監修: 杉野法広 山口大学 産科婦人科学

著者校正/監修レビュー済:2022/01/05
参考ガイドライン:
  1. 日本小児内分泌学会:性分化疾患対応の手引き 
  1. 日本産科婦人科学会/日本産婦人科医会:産婦人科診療ガイドライン 婦人科外来編 2020
  1. 日本小児内分泌学会:21-水酸化酵素欠損症の診断・治療のガイドライン 2021年改訂版
患者向け説明資料

概要・推奨   

  1. 性分化疾患は、その取扱いについて経験が豊富な施設で対応すべき疾患である(推奨度1)。本症のケアには、多職種の医療者からなるチーム医療が必要である。
  1. Y染色体成分を含む腹腔内性腺を有する患者では性腺腫瘍発生の可能性があり、厳重な経過観察をする。リスクの高い群では、予防的性腺摘除が推奨される(推奨度1)。
  1. 性分化疾患の診療では、患者と家族への心理社会的サポートが必須である(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。
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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。
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(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
深見真紀 : 研究費・助成金など(武田科学振興財団),奨学(奨励)寄付など(JCRファーマ(株))[2021年]
監修:杉野法広 : 研究費・助成金など(浜田市,あすか製薬)[2021年]

改訂のポイント:
  1. 定期レビューを行い、語句などのアップデートを行った。また、産婦人診療ガイドラインと21-水酸化酵素欠損症の診断・治療のガイドラインに基づき、文章の加筆修正を行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 性分化疾患(disorders of sex developmentあるいは differences of sex development, DSD)は、染色体、性腺、または解剖学的性が非典型的である先天的状態と定義される。
  1. 性染色体異常に伴う性分化疾患(性染色体性性分化疾患)、46,XY性分化疾患、46,XX性分化疾患の3つに大別される。
  1. 本症は、遺伝性疾患として生じるほか、妊娠母体や本人のホルモン産生腫瘍などによって生じる。46,XY性分化疾患と46,XX性分化疾患では原因不明の例が多い。
  1. 新生児の外性器形態異常もしくは二次性徴発来遅延や原発性無月経が受診の端緒となることが多い。成人期に不妊や染色体検査で見出される場合もある。
 
非典型的な外性器を呈する新生児

出生当日の新生児。陰核・陰唇肥大を伴う非典型的外性器である。本例は染色体検査により45,X/46,XY/47,XYY核型を有する性染色体性性分化疾患と判明した。

出典

img1:  上原茂樹先生ご提供
 
 
 
  1. 単独の疾患として現れることもあるが、ターナー症候群やカルマン症候群など症候群の症状の一つとして認められる場合もある。
問診・診察のポイント  
  1. 性分化疾患は、その診療について経験が豊富な医療機関で扱うべき疾患である。本症のケアには、多職種の医療者からなるチーム医療が必要である。

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文献 

著者: Christopher P Houk, Ieuan A Hughes, S Faisal Ahmed, Peter A Lee, Writing Committee for the International Intersex Consensus Conference Participants
雑誌名: Pediatrics. 2006 Aug;118(2):753-7. doi: 10.1542/peds.2006-0737.
Abstract/Text
PMID 16882833  Pediatrics. 2006 Aug;118(2):753-7. doi: 10.1542/peds.20・・・
著者: Sabine M P F de Muinck Keizer-Schrama
雑誌名: Horm Res. 2007;68 Suppl 5:80-3. doi: 10.1159/000110584. Epub 2007 Dec 10.
Abstract/Text BACKGROUND: Management of puberty in the hypogonadal girl remains controversial. Estrogens have profound effects on growth and development. Oral estrogens, the most widely used form, undergo first-pass metabolism in the liver and alter many aspects of hepatic function. Transdermal estrogens are not subject to first-pass metabolism and are effective at mimicking spontaneous pubertal estrogen levels resulting in normal pubertal development. Age-appropriate induction of puberty should be initiated at 12 to 13 years of age; delaying puberty any longer may compromise quality of life during adolescence. Estrogens should be started at a low dose, approximately one-tenth to one-eighth of the adult replacement dose, and then increased gradually over a period of 2 to 4 years. Generally, progestins are added after 2 years of estrogen therapy. With these treatment regimens, breast development typically proceeds at a normal pace; however, the effects on uterine dimensions are less clear. Concomitant treatment with oral dehydroepiandrosterone (or dehydroepiandrosterone sulfate) advances pubic hair development in the adolescent girl with panhypopituitarism.
CONCLUSIONS: In the hypogonadal girl, puberty should be induced with very low doses of transdermal estradiol at 12 to 13 years of age with gradual dose escalations over 2 to 4 years. Combination estrogen/androgen therapy in girls with hypogonadism should be explored in future research.

Copyright (c) 2007 S. Karger AG, Basel.
PMID 18174716  Horm Res. 2007;68 Suppl 5:80-3. doi: 10.1159/000110584.・・・
著者: Ieuan A Hughes
雑誌名: Horm Res. 2007;68 Suppl 5:84-9. doi: 10.1159/000110585. Epub 2007 Dec 10.
Abstract/Text BACKGROUND: Congenital adrenal hyperplasia (CAH), the most common cause of ambiguous genitalia of the newborn, requires rapid assessment by a multidisciplinary team including a neonatologist, paediatric endocrinologist, paediatric urologist and geneticist. There is also a role for the clinical psychologist with psychosexual counselling experience as families cope with disorders of sex development. This brief review summarises the continuum of disorders that are manifested in patients with CAH according to age and sex, with emphasis on the lifetime nature of the issues that accompany this disorder and on the long-lasting ramifications of pediatric management decisions for both males and females.
CONCLUSIONS: There are many management aspects of caring for patients with CAH that clearly fall into the purview of paediatricians or adult-care physicians. There are also areas where responsibilities overlap and require several professionals providing coordinated care.

Copyright (c) 2007 S. Karger AG, Basel.
PMID 18174717  Horm Res. 2007;68 Suppl 5:84-9. doi: 10.1159/000110585.・・・
著者: I A Hughes, C Houk, S F Ahmed, P A Lee, LWPES Consensus Group, ESPE Consensus Group
雑誌名: Arch Dis Child. 2006 Jul;91(7):554-63. doi: 10.1136/adc.2006.098319. Epub 2006 Apr 19.
Abstract/Text
PMID 16624884  Arch Dis Child. 2006 Jul;91(7):554-63. doi: 10.1136/adc・・・
著者: J L Ross, L M Long, M Skerda, F Cassorla, D Kurtz, D L Loriaux, G B Cutler
雑誌名: J Pediatr. 1986 Dec;109(6):950-3.
Abstract/Text We randomly assigned 16 girls with Turner syndrome, age 5 to 15 years, to receive treatment with 100 ng/kg/day ethinyl estradiol or placebo for 6 months, with crossover after a 2-month interim period. We assessed growth by measurement of the 4-week lower leg growth rate and by height velocity. Bone age was determined at the beginning and end of treatment. Growth rate during ethinyl estradiol treatment was approximately 70% greater than during placebo (P less than 0.001), without any bone age advancement relative to that with placebo. The change in predicted height was significantly greater after 6 months treatment with ethinyl estradiol than after treatment with placebo (mean +/- SEM, +0.35 +/- 0.38 cm vs. -0.85 +/- 0.32 cm, P less than 0.03). Breast budding occurred in six patients. We conclude that it may be feasible to begin low-dose estrogen therapy to promote growth at an earlier age than would be conventionally used to induce pubertal development. These data are still relatively short term, however; until long-term data are available, it would be premature to make definitive recommendations regarding the dose and timing of estrogen treatment in Turner syndrome.

PMID 3537251  J Pediatr. 1986 Dec;109(6):950-3.
著者: Robert L Rosenfield, Nancy Devine, Joanne Julius Hunold, Nelly Mauras, Thomas Moshang, Allen W Root
雑誌名: J Clin Endocrinol Metab. 2005 Dec;90(12):6424-30. doi: 10.1210/jc.2005-1081. Epub 2005 Sep 27.
Abstract/Text CONTEXT: Optimizing pubertal estrogen replacement in girls with Turner syndrome is important.
OBJECTIVE: The study objective was to test the hypotheses that physiological estradiol replacement administered early with GH will preserve height potential as much as if administered late and that it will bring about a greater height gain than standard oral estrogen therapy combined with GH.
DESIGN: The study was randomized to early or late estrogen treatment; follow-up was at 3.5 yr or later.
SETTING: This was a multicenter outpatient study.
PATIENTS: Turner syndrome girls 12.0-12.9 yr (n = 7) or 14.0-14.9 yr (n = 7) of age who began GH before age 12.0 yr were the patients. The girls were matched to National Cooperative Growth Study registry patients who began GH and oral conjugated estrogen at similar ages and were similarly followed to adult or near-adult height.
INTERVENTIONS: Depot estradiol, 0.2 mg/month i.m., was given initially and gradually increased; GH was 0.05 mg/kg daily.
MAIN OUTCOME VARIABLE: Adult or near-adult height was the main outcome variable.
RESULTS: Depot estradiol treatment resulted in height significantly taller than predicted at 12 yr of age (P < 0.02). All height potential was gained in the first 2 yr of the study, during which the early group grew 3.5 cm more than the late group, which was receiving GH alone (P < 0.01). The early depot estradiol group also gained 5.9 cm more height after starting estrogen than did the early National Cooperative Growth Study group (P < 0.05). Although feminization proceeded slowly on the lowest dose of estradiol, it advanced normally thereafter.
CONCLUSIONS: These results suggest that very low-dose parenteral estradiol permits relatively age-appropriate feminization without interfering with the effect of GH on the enhancement of height potential.

PMID 16189255  J Clin Endocrinol Metab. 2005 Dec;90(12):6424-30. doi: ・・・
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: Kim Freriks, Janneke Timmermans, Catharina C M Beerendonk, Chris M Verhaak, Romana T Netea-Maier, Barto J Otten, Didi D M Braat, Dominique F C M Smeets, Dirk H P M Kunst, Ad R M M Hermus, Henri J L M Timmers
雑誌名: J Clin Endocrinol Metab. 2011 Sep;96(9):E1517-26. doi: 10.1210/jc.2011-0346. Epub 2011 Jul 13.
Abstract/Text CONTEXT: Besides short stature and gonadal dysgenesis, Turner syndrome (TS) is associated with various abnormalities. Adults with TS have a reduced life expectancy, mainly related to structural abnormalities of the heart and aorta, and an increased risk of atherosclerosis.
OBJECTIVE: Our objective was to investigate the yield of an initial standardized multidisciplinary screening in adult TS patients.
DESIGN AND SETTING: This was an observational study at a multidisciplinary care unit for adult women with TS.
PARTICIPANTS: Participants were adult women with TS (n = 150). Mean age was 31.0 ± 10.4 yr, with 47% karyotype 45,X.
INTERVENTIONS: All women were consulted by an endocrinologist, a gynecologist, a cardiologist, an otorhinolaryngologist, and when indicated, a psychologist. The screening included magnetic resonance imaging of the heart and aorta, echocardiography, electrocardiogram, dual-energy x-ray absorptiometry, renal ultrasound, audiogram, and laboratory investigations according to international expert recommendations.
MAIN OUTCOME MEASURES: New diagnoses and prevalence of TS-associated morbidity were evaluated.
RESULTS: Thirty percent of patients currently lacked medical follow-up, and 15% lacked estrogen replacement therapy in the recent last years. The following disorders were newly diagnosed: bicuspid aortic valve (n = 13), coarctation of the aorta (n = 9), elongation of the transverse aortic arch (n = 27), dilation of the aorta (n = 34), osteoporosis (n = 8), osteopenia (n = 56), renal abnormalities (n = 7), subclinical hypothyroidism (n = 33), celiac disease (n = 3), glucose intolerance (n = 12), dyslipidemia (n = 52), hypertension (n = 39), and hearing loss warranting a hearing aid (n = 8). Psychological consultation was needed in 23 cases.
CONCLUSIONS: Standardized multidisciplinary evaluation of adult women with TS as advocated by expert opinion is effective and identifies significant morbidity. Girls with TS benefit from a careful transition to ongoing adult medical care.

PMID 21752892  J Clin Endocrinol Metab. 2011 Sep;96(9):E1517-26. doi: ・・・
著者: Hideya Sakakibara, Hiroshi Yoshida, Maki Takei, Yukiko Katsuhata, Makiko Koyama, Tomoko Nagata, Masahiko Ishikawa, Fumiki Hirahara
雑誌名: J Obstet Gynaecol Res. 2011 Jul;37(7):836-42. doi: 10.1111/j.1447-0756.2010.01448.x. Epub 2011 Mar 16.
Abstract/Text AIM: Since women with Turner Syndrome (TS) have various complications, they require comprehensive medical evaluation and multidisciplinary treatment. Although TS patients receive adequate care in childhood, many adults with TS do not. Since most TS adults attend gynecologists for hormone replacement therapy, we suggest gynecologists take primary responsibility for their management. In an attempt to provide TS patients with a comprehensive treatment regimen, we started multidisciplinary medical management in the Reproductive Health Clinic at Yokohama City University Hospital. To evaluate the efficacy of this medical care system, a retrospective analysis was conducted.
METHODS: The clinical profiles of 57 TS patients were examined. The past histories, complications and clinical data of these patients were extracted from their medical records and examined clinically. Bone mineral density measurements of lumbar vertebrae (L(2-4)), anti-thyroid antibody titer measurements, hearing tests and cardiovascular MRI were also performed.
RESULTS: Mean follow-up duration was 5.1 years (range, 1-8 years). At the time of transition, patients with complications developed in childhood, such as amenorrhea, osteopenia/osteoporosis, otitis media, thyroid dysfunction and cardiovascular disease were identified. All these complaints were successfully followed up in our adult care system. Several complications common to TS adults, such as glucose intolerance, liver dysfunction, hyperlypidemia and hypertension could be identified by our screening system. Patients were referred to specialists when necessary.
CONCLUSION: Multidisciplinary health management in our Reproductive Health Clinic improved the status of medical care for TS adults.

© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.
PMID 21410832  J Obstet Gynaecol Res. 2011 Jul;37(7):836-42. doi: 10.1・・・

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