兒童Van Wyk-Grumbach綜合征1例報(bào)告并文獻(xiàn)復(fù)習(xí)

張東光 楊 玉 楊 利

江西省兒童醫(yī)院內(nèi)分泌遺傳代謝科（江西南昌 330006）

兒童Van Wyk-Grumbach綜合征1例報(bào)告并文獻(xiàn)復(fù)習(xí)

張東光 楊 玉 楊 利

江西省兒童醫(yī)院內(nèi)分泌遺傳代謝科（江西南昌 330006）

目的探討Van Wyk-Grumbach綜合征（VWGS）的早期診斷和治療。方法回顧分析1例VWGS患兒的臨床資料，并復(fù)習(xí)相關(guān)文獻(xiàn)。結(jié)果患兒，女，9歲，因身高增長緩慢、肥胖3年，伴乳房增大6個(gè)月、陰道出血3個(gè)月就診。游離甲狀腺素（FT4）0.46 ng/dL，促甲狀腺素（TSH）＞150 mIU/L；GnRH激發(fā)試驗(yàn)提示性腺軸未啟動(dòng)；血泌乳素、雌二醇明顯升高；骨齡延遲；彩色超聲示子宮、卵巢增大，可見卵巢囊腫；垂體MRI示腺垂體增生。予左甲狀腺素鈉治療2個(gè)月后甲狀腺功能恢復(fù)正常，復(fù)查彩超示雙卵巢明顯縮小，體質(zhì)量減輕6 kg，未再陰道出血；3個(gè)月后雙卵巢至正常大小，鞍區(qū)MRI占位縮?。?個(gè)月后復(fù)查彩色超聲示子宮、卵巢大小正常，無卵巢囊腫，鞍區(qū)MRI占位消失。結(jié)論VWGS是長期未經(jīng)治療的嚴(yán)重原發(fā)性甲狀腺功能減退癥少見的并發(fā)癥，好發(fā)于青春期女童，甲狀腺素替代治療有效。

原發(fā)性甲狀腺功能減退癥； Van Wyk-Grumbach綜合征； 兒童

Van Wyk-Grumbach綜合征（Van Wyk-Grumbach syndrome，VWGS）是長期未經(jīng)治療的嚴(yán)重原發(fā)性甲狀腺功能減退癥少見的并發(fā)癥，可發(fā)生在不同年齡，但好發(fā)于青春期女童。疾病特征為典型的甲狀腺功能減退面容，生長遲緩，假性性早熟，乳房發(fā)育，有時(shí)伴陰道流血（不伴陰毛或腋毛）；影像學(xué)檢查示骨齡發(fā)育延遲，卵巢或睪丸異常發(fā)育增大，可出現(xiàn)卵巢囊腫，并繼發(fā)垂體瘤樣增生。VWGS臨床易被誤診。

1 臨床資料

患兒，女，9歲，因身高增長緩慢、肥胖3年，乳房增大6個(gè)月，陰道出血3個(gè)月就診。無外傷及陰道異物史，否認(rèn)服用激素類藥物史。起病來精神好、食欲佳、睡眠好，大便干結(jié)，每2～3天1次，小便正常。患兒出生史無特殊，新生兒篩查無異常。生長發(fā)育較同齡兒落后，8個(gè)月能獨(dú)坐、10個(gè)月會(huì)爬、2歲能獨(dú)走，智力較同齡兒落后，學(xué)習(xí)成績差。入院體格檢查：體溫36.8℃，脈搏100次/min，呼吸20次/min，血壓108/74 mmHg；身高121.5 cm（＜－2SD），上部量67.2 cm，下部量54.3 cm；體質(zhì)量47 kg（＞+2SD），體質(zhì)指數(shù)31.8 kg/m2。神志清楚，反應(yīng)稍遲鈍；有黏液水腫面容，無皮疹、無多毛、無牛奶咖啡斑，皮膚粗糙，頭發(fā)干澀、稀疏，眼距稍寬，鼻梁塌，無黑棘皮、無紫紋；甲狀腺無腫大；雙乳B3期；心音稍低鈍，心律齊；雙肺呼吸音清；腹膨隆，腹部脂肪堆積，肝脾肋下未及腫大；肌力及肌張力正常；腋毛A1期，陰毛PH2期。實(shí)驗(yàn)室檢查：血紅蛋白70 g/L；丙氨酸氨基轉(zhuǎn)移酶 55 U/L，天冬氨酸氨基轉(zhuǎn)移酶 70 U/L；腎功能、血糖、血脂、電解質(zhì)無異常；乙肝抗原抗體、甲胎蛋白、癌胚抗原無異常；三碘甲腺原氨酸 0.15 ng/mL，游離三碘甲腺原氨酸0.19 pg/mL，甲狀腺素1.40 μg/dL，游離甲狀腺素 0.46 ng/dL，促甲狀腺素＞150.00 mIU/L，甲狀腺球蛋白抗體 596.343 IU/mL，甲狀腺微粒體抗體241.32 IU/mL；皮質(zhì)醇（8:00AM），10.94 μg/dL；促性腺激素釋放刺激試驗(yàn)，促黃體生成素峰值0 mIU/mL，卵泡生成素峰值6.42 mIU/mL；絨毛膜促性腺激素 3.8 mIU/mL，泌乳素84.06 ng/mL，孕酮3.04 ng/mL，睪酮17.75 ng/dL，雌二醇731.83 pg/mL，雄烯二酮2.64 ng/mL，硫酸脫氫表雄酮56.9 μg/dL，17羥孕酮0.92 ng/mL。骨齡7歲。彩色超聲：子宮約48mm×22mm×22mm，左側(cè)卵巢區(qū)見130mm×71mm囊實(shí)性包塊，其內(nèi)側(cè)約85mm×73mm實(shí)質(zhì)性為主并囊性暗區(qū)，外側(cè)約70mm×58mm的囊性暗區(qū)，其間見光帶，右側(cè)卵巢區(qū)見70mm×50mm囊泡暗區(qū)；頸部未及甲狀腺回聲。垂體磁共振成像（MRI）示腺垂體上緣膨隆，信號(hào)均勻。臨床診斷VWGS。

給予左甲狀腺素鈉治療，從25 μg/d開始，逐漸加量，根據(jù)臨床癥狀及甲狀腺激素水平調(diào)整用量，至目前62.5 μg/d。治療2個(gè)月后游離甲狀腺素（FT4）、促甲狀腺激素（TSH）恢復(fù)正常，PRL下降，復(fù)查彩超雙卵巢明顯縮小，體質(zhì)量下降6 kg，未再陰道出血；治療3個(gè)月后復(fù)查雙卵巢正常大小，鞍區(qū)MRI占位縮??；治療6個(gè)月后子宮、卵巢大小正常，無卵巢囊腫，鞍區(qū)MRI占位消失。

2 討論

1905年Kendle[1]報(bào)道1例9歲女孩，5歲時(shí)月經(jīng)初潮，乳房發(fā)育，甲狀腺功能減退。經(jīng)甲狀腺素替代治療后癥狀改善。1960年由Van Wyk和Grumbach首次將其命名為VWGS[2]。VWGS的主要特征為長期未經(jīng)治療的甲狀腺功能減退癥患者出現(xiàn)同性性早熟和卵巢囊腫/多囊卵巢或睪丸增大。目前，雖然VWGS確切的發(fā)病機(jī)制仍不甚清楚，其治療方法簡單、明確。使用左甲狀腺素治療能逐漸緩解臨床癥狀，改善內(nèi)分泌激素的異常[3,4]。

關(guān)于VWGS的發(fā)病機(jī)制，存在以下假說：①“疊加論”。最初Van Wyk和Grumbach假設(shè)腦垂體在甲狀腺激素不足時(shí)缺乏特異的負(fù)反饋機(jī)制[2]，導(dǎo)致促性腺激素及促甲狀腺激素（thyrotropin releasing hormone，TRH）的疊加分泌是VWGS的發(fā)病原因。持續(xù)高TRH水平能同時(shí)刺激TSH和卵泡刺激素（FSH）分泌，卵巢顆粒細(xì)胞核內(nèi)的甲狀腺素受體受高水平TSH刺激，導(dǎo)致雄烯二酮轉(zhuǎn)化為雌酮、雌二醇增多[3]。②高泌乳素血癥。長期的甲狀腺功能減退反饋調(diào)節(jié)導(dǎo)致TRH升高，進(jìn)而導(dǎo)致催乳素細(xì)胞增生，PRL升高。對(duì)小鼠研究發(fā)現(xiàn)，高水平的PRL可能通過上調(diào)卵巢LH受體增強(qiáng)其對(duì)循環(huán)中促性腺激素的敏感性，提示因TRH升高導(dǎo)致的高泌乳素血癥為可能的發(fā)病機(jī)制[5-7]。③糖蛋白激素的“分子模擬”。TSH、FSH、LH均具有相同的α亞單位，高水平的TSH能通過刺激FSH受體導(dǎo)致卵巢過度受刺激和性早熟[8]。Smits等[9]曾提出FSH受體突變及對(duì)TSH的敏感性增強(qiáng)是卵巢過度刺激的原因，但之后多項(xiàng)研究對(duì)VWGS患者FSH受體基因外顯子和內(nèi)含子測(cè)序并未發(fā)現(xiàn)基因突變[10-12]。本例患兒高水平的TSH、E2、PRL與文獻(xiàn)報(bào)道一致。雖然在血清高水平TSH時(shí)，正常的FSH受體能被刺激而發(fā)生一系列反應(yīng)，但是許多甲狀腺功能嚴(yán)重低下的患兒（即使在TSH＞1 000 mIU/L時(shí)）未顯示出性腺發(fā)育的明顯跡象。以往研究報(bào)道VWGS患者的血清TSH水平無顯著升高[10]。這些VWGS選擇性發(fā)生的機(jī)制仍需進(jìn)一步探索和研究。

有研究者歸納了1978－2014年間34例VWGS患兒（年齡3～17歲，女31例、男3例）的臨床特點(diǎn)，女性典型表現(xiàn)為陰道出血、乳房發(fā)育、體質(zhì)量增加、生長緩慢、疲倦、腹部包塊或腹痛，除1例患兒外，均存在卵巢多囊性增大或卵巢多房性腫物；男性表現(xiàn)為第二性征發(fā)育、睪丸增大，1例同時(shí)存在矮身材、體質(zhì)量增加、骨齡延遲。實(shí)驗(yàn)室檢查顯示22例患兒TSH＞100 mIU/mL，13例PRL升高，12例促性腺激素水平升高。男性病例數(shù)少可能與甲狀腺疾病在女性中多見有關(guān)[13]。原發(fā)性甲狀腺功能減退并性早熟的發(fā)生率為24%[14]。骨齡延遲是診斷VWGS的重要依據(jù)，因在性早熟兒童中VWGS是存在骨齡延遲的特例[2,15]。同時(shí)，較其他病因所致的性早熟，VWGS患兒不伴生長突增[16]。典型病例可繼發(fā)垂體增生（pituitary hyperplasia secondaryto primary hypothyroidism，PPH）[17-19]，且垂體增生程度與甲狀腺功能減低癥的嚴(yán)重程度相關(guān)[19,20]。國內(nèi)報(bào)道山東地區(qū)22例PPH中8例伴性早熟患兒具有相對(duì)高的TSH、FSH、PRL、雌二醇（E2）水平，MRI顯示的垂體高度及彩超顯示的卵巢體積亦高于正常對(duì)照組；PPH患兒垂體高度與血清FT3、FT4水平呈顯著負(fù)相關(guān)，與血清PRL水平呈顯著正相關(guān)[21]。本例患兒為青春期女童，有生長遲緩、肥胖、提前出現(xiàn)乳房發(fā)育、陰道出血；實(shí)驗(yàn)室檢查提示存在甲狀腺功能減退，性腺軸未啟動(dòng)；影像學(xué)檢查提示骨齡延遲、垂體增生、卵巢囊腫，根據(jù)典型的臨床表現(xiàn)初步診斷為VWGS。

VWGS的治療為甲狀腺素替代治療。國內(nèi)指南推薦兒童替代劑量約2.0 μg/（kg·d），根據(jù)患兒體質(zhì)量和甲狀腺功能調(diào)整用量。甲狀腺素治療能使所有癥狀緩解、體征消失[13,16,21-23]。但需注意伴腫瘤標(biāo)志物陽性的卵巢大囊腫通常雖提示惡性可能，仍需首先排除甲狀腺功能減退癥的存在。既往曾報(bào)道包括糖鏈抗原125（CA-125）、乳酸脫氫酶（lactate dehydrogenase，LDH）、甲胎蛋白（alpha fetal protein，AFP）、抑制素（inhibin，Inh）等腫瘤標(biāo)志物在VWGS患者中升高，而甲狀腺激素替代治療后恢復(fù)正常，并未有腫瘤發(fā)生[24-28]。如Tran等[24]報(bào)道1例10歲VWGS女孩，超聲顯示單側(cè)卵巢多囊性腫物（10.6 cm×8.2 cm×10.7 cm）伴血清抑制素A、抑制素B水平明顯升高而不能排除卵巢顆粒細(xì)胞瘤可能，在經(jīng)甲狀腺素替代治療8個(gè)月后腫物完全消退，22個(gè)月后抑制素水平正常，避免了手術(shù)。對(duì)于VWGS患者，多囊性的卵巢可較正常稍大或直徑達(dá)20 cm，通常甲狀腺素替代治療平均2個(gè)月后增大的卵巢恢復(fù)正常，但部分病例可長達(dá)1年，延誤診斷可能導(dǎo)致不必要的卵巢切除術(shù)[6,22,29]。垂體恢復(fù)正常的時(shí)間文獻(xiàn)報(bào)道不一。國內(nèi)報(bào)道6例PPH病例治療后平均（9.3±2.7）個(gè)月垂體恢復(fù)至正常[23]。本例患兒經(jīng)左甲狀腺素鈉治療6個(gè)月后復(fù)查子宮、卵巢大小正常，無卵巢囊腫，鞍區(qū)MRI占位消失，恢復(fù)時(shí)間與文獻(xiàn)報(bào)道一致，提示原發(fā)性甲減是引起這些改變的主要原因，從而驗(yàn)證了VWGS這一診斷。

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Van Wyk-Grumbach syndrome in children: a case report and literature review

ZHANG Dongguang, YANG Yu, YANG Li
(Jiangxi Provincial Children’s Hospital, Nanchang 330006, Jiangxi, China)

ObjectiveTo explore the early diagnosis and treatment of Van Wyk-Grumbach syndrome (VWGS).MethodsThe clinical data of a child with VWGS were retrospectively analyzed. The related literatures were reviewed.ResultsNine-year-old female presented with growth retardation and obesity for 3 years, combined with breast development for 6 months and vaginal bleeding for 3 month. The level of free thyroxine (FT4) was 0.46 ng/dL and thyrotropin (TSH)＞150 mIU/L. The GnRH stimulation test showed that the gonad axis was not activated. The serum prolactin and estradiol were significantly increased. Bone age was delayed. Color Doppler ultrasound showed enlarged uterus and enlarged ovary, and ovarian cyst was seen. Pituitary MRI showed hyperplasia of the pituitary gland. The patient received the treatment of Euthyrox, and 2 months later, thyroid function was back to normal, ovaries were significantly reduced by reexamine of color doppler ultrasound, body weight was reduced by 6 kg, and there was no vaginal bleeding. Three months later, both ovaries returned to normal size, and pituitary MRI showed hyperplasia of adenohypophysis was improved. After 6 months, both of uterus and ovary were turn to normal size, ovarian cyst disappeared, and pituitary MRI showed normal.ConclusionsVWGS is a rare complication of severe primary hypothyroidism untreated for long time and it mainly occurs in adolescent girls. Thyroid replacement therapy is effective.

primary hypothyroidism; Van Wyk-Grumbach syndrome; child

10.3969/j.issn.1000-3606.2017.03.011

2016-10-07)

(本文編輯：蔡虹蔚)

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