引起矮小的原因很多,要治疗必须查清病因,做出正确诊断,然后再考虑如何治疗。而要查清病因首先要通过病史调查、体格和化验检查,根据详细的资料和化验结果,综合分析,判断引起儿童矮小的原因,最后确定治疗原则。 矮小儿童到医院就诊时家长需提供以下资料:1.母亲妊娠情况,还有婴儿出生时情况,是否难产、窒息以及采用何种分娩方式,出生时身高和体重等。2.每年身高增长速度,测定时需脱去鞋子。3.父母身高和青春发育情况,家族中是否有矮身材。4.智力发育情况,有无慢性肝炎、肾脏疾病和哮喘病。5.是否用过影响生长发育药物,如泼尼松(强的松)、地塞米松等糖皮质激素等。 孩子到了医院,常规进行血、尿检查,肝、肾功能检测和甲状腺激素水平检测,女孩要做核型分析。其次需对左手腕掌指进行X线照片,以了解骨龄,判断孩子骨骼生长情况,骨骺闭合的程度和生长潜力。如有需要还要抽血检测甲状腺激素、性激素、生长因子等的水平。此外,如考虑为生长激素缺乏性身材矮小,需做生长激素激发试验才能诊断。矮小儿童都要进行颅部的MRI检查,以排除先天发育异常或肿瘤的可能性。需要注意:有些检查可能需要空腹,请注意检查前避免进食,有的检查当天可能无法出结果,请您做好时间安排。
医学上“矮身材”的判断是用正常儿童的身高参考值来衡量的。我国约每10年进行一次全国性的正常儿童、青少年生长发育情况调查,所得到的资料用医学统计方法加以整理。就身高而言,按年龄和性别分组,计算出每组的平均值和各个百分位数值;在医学上身高低于第3百分位数称为矮身材。比如10岁男孩的平均身高为140.2厘米(第50百分位), 如低于128.6厘米(第3百分位)为矮身材。 对于家长来讲,孩子身高明显低于同年龄、同性别儿童,或年生长速率低于4-5厘米,就应到正规医院儿科生长发育门诊处咨询并接受相关检查。检查项目包括询问家族史及生长发育史、常规体格检查、骨龄(左手腕、掌、指骨)和蝶鞍X线像、甲状腺功能、生长激素、染色体检查和其他特殊检查等,以判断生长发育状况、垂体内分泌功能及有无其他疾病等。 对于身高偏低但尚在正常范围者,多不主张进行特殊干预,而仅需调整营养膳食结构,适当补充维生素和微量元素,加强锻炼,改善睡眠,以及治疗潜在的疾病,并注意监测生长速率。 对于生长激素缺乏症应尽早应用基因重组人生长激素进行正规治疗,使用第1年平均可增长10~12厘米。美国食品与药物管理局(FDA)批准和我国儿科学会推荐应用生长激素的其他适应征包括先天性卵巢发育不全综合征、生长落后的小于胎龄儿(出生体重低于相对胎龄体重)、特发性矮身材(非生长激素缺乏性身材矮小)、慢性肾功能衰竭导致的生长落后及一些遗传性身材矮小等。 对于不同的原发疾病、开始治疗的时间、以及应用剂量等可产生不同的效果。一般说来开始治疗时间越早、在一定范围内剂量越大,治疗效果越好。性早熟的儿童在采用药物抑制性发育和骨骼成熟的同时亦可根据具体情况合并使用生长激素,以促进身高增长。 生长激素已被近十万儿童广泛使用,明显的药物副作用十分少见,部分孩子使用后可能有注射局部红肿,极少数儿童出现头痛、水肿和关节痛等,多在减少剂量或暂时停用药物后消失。目前没有证据表明在长期接受生长激素治疗后有白血病、颅内肿瘤复发、股骨头滑脱或糖尿病的危险增加。但需说明,生长激素是一种治疗性药物,且长期使用花费较大,必须在专科医生的严格指导和监测下使用。
卫生部办公厅印发的《性早熟诊疗指南(试行)》 卫生部办公厅关于印发《性早熟诊疗指南(试行)》的通知 中华人民共和国卫生部www.moh.gov.cn 卫办医政发〔2010〕195号各省、自治区、直辖市卫生厅局,新疆生产建设兵团卫生局:为科学、规范地做好性早熟诊疗工作,促进儿童健康成长,我部制定了《性早熟诊疗指南(试行)》。现印发给你们,供医疗机构在临床诊疗工作中参考使用。二〇一〇年十二月七日 性早熟诊疗指南(试行)一、定义性早熟(precocious puberty)是指男童在9岁前,女童在8岁前呈现第二性征。按发病机理和临床表现分为中枢性(促性腺激素释放激素依赖性)性早熟和外周性(非促性腺激素释放激素依赖性)性早熟,以往分别称真性性早熟和假性性早熟。中枢性性早熟(central precocious puberty, CPP)具有与正常青春发育类同的下丘脑-垂体-性腺轴(HPGA)发动、成熟的程序性过程,直至生殖系统成熟;即由下丘脑提前分泌和释放促性腺激素释放激素(GnRH),激活垂体分泌促性腺激素使性腺发育并分泌性激素,从而使内、外生殖器发育和第二性征呈现。外周性性早熟是缘于各种原因引起的体内性甾体激素升高至青春期水平,故只有第二性征的早现,不具有完整的性发育程序性过程。二、病因(一)中枢性性早熟。1.中枢神经系统器质性病变,如下丘脑、垂体肿瘤或其他中枢神经系统病变。2.由外周性性早熟转化而来。3.未能发现器质性病变的,称为特发性中枢性性早熟(idiopathic CPP, ICPP)。4.不完全性中枢性性早熟,是CPP的特殊类型,指患儿有第二性征的早现,其控制机制也在于下丘脑-垂体-性腺轴的发动,但它的性征发育呈自限性;最常见的类型为单纯性乳房早发育,若发生于2岁内女孩,可能是由于下丘脑-性腺轴处于生理性活跃状态,又称为“小青春期”。女孩以ICPP为多,占CPP的80%-90%以上;而男孩则相反,80%以上是器质性的。(二)外周性性早熟。1.按第二性征特征分类:早现的第二性征与患儿原性别相同时称为同性性早熟,与原性别相反时称为异性性早熟。2.常见病因分类2.1女孩(1)同性性早熟(女孩的第二性征):见于遗传性卵巢功能异常如McCune-Albright综合征、卵巢良性占位病变如自律性卵巢囊肿、分泌雌激素的肾上腺皮质肿瘤或卵巢肿瘤、异位分泌人绒毛膜促性腺激素(HCG)的肿瘤以及外源性雌激素摄入等。(2)异性性早熟(男性的第二性征):见于先天性肾上腺皮质增生症、分泌雄激素的肾上腺皮质肿瘤或卵巢肿瘤,以及外源性雄激素摄入等。2.2男孩(1)同性性早熟(男性第二性征):见于先天性肾上腺皮质增生症(较常见)、肾上腺皮质肿瘤或睾丸间质细胞瘤、异位分泌HCG的肿瘤,以及外源性雄激素摄入等。(2)异性性早熟(女性第二性征):见于产生雌激素的肾上腺皮质肿瘤或睾丸肿瘤、异位分泌HCG的肿瘤以及外源性雌激素摄入等。三、临床表现和诊断依据(一)中枢性性早熟。1.第二性征提前出现(符合定义的年龄),并按照正常发育程序进展,女孩:乳房发育,身高增长速度突增,阴毛发育,一般在乳房开始发育2年后初潮呈现。男孩:睾丸和阴茎增大,身高增长速度突增,阴毛发育,一般在睾丸开始增大后2年出现变声和遗精。2.有性腺发育依据,女孩按B超影像判断,男孩睾丸容积≥4 ml。3.发育过程中呈现身高增长突增。4.促性腺激素升高至青春期水平。5.可有骨龄提前,但无诊断特异性。不完全性中枢性性早熟中最常见的类型为单纯性乳房早发育,表现为只有乳房早发育而不呈现其他第二性征,乳晕无着色,呈非进行性自限性病程,乳房多在数月后自然消退。(二)外周性性早熟。1.第二性征提前出现(符合定义的年龄)。2.性征发育不按正常发育程序进展。3.性腺大小在青春前期水平。4.促性腺激素在青春前期水平。四、诊断流程和辅助检查(一)确定中枢性或外周性性早熟,除按临床特征初步判断外,需作以下辅助检查:1.基础性激素测定。基础促黄体生成激素(LH)有筛查意义,如LH<0.1 IU/L提示未有中枢性青春发动,LH>3.0-5.0IU/L可肯定已有中枢性发动。凭基础值不能确诊时需进行激发试验。β-HCG和甲胎蛋白(AFP)应当纳入基本筛查,是诊断分泌HCG生殖细胞瘤的重要线索。雌激素和睾酮水平升高有辅助诊断意义。2.促性腺激素释放激素(GnRH)激发试验。(1)方法:以GnRH 2.5-3.0μg/kg (最大剂量100μg)皮下或静脉注射,于注射的0、30、60和90min测定血清LH和卵泡刺激素(FSH)水平。(2)判断:如用化学发光法测定,激发峰值LH>3.3-5.0 IU/L是判断真性发育界点,同时LH/FSH比值>0.6时可诊断为中枢性性早熟。目前认为以激发后30-60min单次的激发值,达到以上标准也可诊断。如激发峰值以FSH升高为主,LH/FSH比值低下,结合临床可能是单纯性乳房早发育或中枢性性早熟的早期,后者需定期随访,必要时重复检查。3.子宫卵巢B超。单侧卵巢容积≥1-3ml,并可见多个直径≥4 mm的卵泡,可认为卵巢已进入青春发育状态;子宫长度>3.4-4cm可认为已进入青春发育状态,可见子宫内膜影提示雌激素呈有意义的升高。但单凭B超检查结果不能作为CPP诊断依据。4.骨龄。是预测成年身高的重要依据,但对鉴别中枢和外周性无特异性。(二)病因学诊断。1.中枢性性早熟病因诊断:确诊为中枢性性早熟后需做脑CT或MRI检查(重点检查鞍区),尤其是以下情况:(1)确诊为CPP的所有男孩。(2)6岁以下发病的女孩。(3)性成熟过程迅速或有其他中枢病变表现者。2.外周性性早熟病因诊断:按照具体临床特征和内分泌激素初筛后进行进一步的内分泌检查,并按需做性腺、肾上腺或其他相关器官的影像学检查。如有明确的外源性性甾体激素摄入史者可酌情免除复杂的检查。五、治疗(一)中枢性性早熟。治疗目标为抑制过早或过快的性发育,防止或缓释患儿或家长因性早熟所致的相关的社会或心理问题(如早初潮);改善因骨龄提前而减损的成年身高也是重要的目标。但并非所有的ICPP都需要治疗。GnRH类似物(GnRHa)是当前主要的治疗选择,目前常用制剂有曲普瑞林和亮丙瑞林的缓释剂。1.以改善成年身高为目的的应用指征:(1)骨龄大于年龄2岁或以上,但需女孩骨龄≤11.5岁,男孩骨龄≤12.5岁者。(2)预测成年身高:女孩<150cm,男孩<160cm。(3)或以骨龄判断的身高SDS<-2SD(按正常人群参照值或遗传靶身高判断)。(4)发育进程迅速,骨龄增长/年龄增长>1。2.不需治疗的指征:(1)性成熟进程缓慢(骨龄进展不超越年龄进展)而对成年身高影响不显者。(2)骨龄虽提前,但身高生长速度亦快,预测成年身高不受损者。因为青春发育是一个动态的过程,故对每个个体的以上指标需动态观察。对于暂不需治疗者均需进行定期复查和评估,调整治疗方案。3.GnRHa剂量:首剂80-100μg/kg,最大量3.75mg;其后每4周注射1次,体重≥30kg者,曲普瑞林每4周肌注3-3.75mg。已有初潮者首剂后2周宜强化1次。但需强调的是,维持剂量应当个体化,根据性腺轴功能抑制情况而定(包括性征、性激素水平和骨龄进展),男孩剂量可偏大。对按照以上处理性腺轴功能抑制仍差者可酌情缩短注射间歇时间或增量。不同的GnRHa缓释剂都有效,产品选择决定于医生用药习惯和患者接受程度(如更接受肌肉或皮下注射)或当地产品供应情况。4.治疗监测和停药决定:治疗过程中每3-6个月测量身高以及性征发育状况(阴毛进展不代表性腺受抑状况);首剂3-6个月末复查GnRH激发试验,LH峰值在青春前期水平提示剂量合适。其后对女孩需定期复查基础血清雌二醇(E2)和子宫、卵巢B超;男孩需复查基础血清睾酮浓度以判断性腺轴功能抑制状况。每半年复查骨龄1次,结合身高增长,预测成年身高改善情况。对疗效不佳者需仔细评估原因,调整治疗方案。首次注射后可能发生阴道出血,或已有初潮者又见出血,但如继后注射仍有出血时应当认真评估。为改善成年身高的目的疗程至少2年,具体疗程需个体化。一般建议在年龄11.0岁,或骨龄12.0岁时停药,可望达最大成年身高,开始治疗较早者(<6岁)成年身高改善较为显著。但骨龄并非绝对的单个最佳依据参数,仍有个体差异。单纯性乳房早发育多呈自限病程,一般不需药物治疗,但需强调定期随访,小部分患儿可能转化为中枢性性早熟,尤其在4岁以后起病者。5.GnRHa治疗中部分患者生长减速明显,小样本资料显示联合应用重组人生长激素(rhGH)可改善生长速率或成年身高,但目前仍缺乏大样本、随机对照研究资料,故不推荐常规联合应用,尤其女孩骨龄>12岁,男孩骨龄>14岁者。有中枢器质性病变的CPP患者应当按照病变性质行相应病因治疗。错构瘤是发育异常,如无颅压增高或其他中枢神经系统表现者,不需手术,仍按ICPP药物治疗方案治疗。蛛网膜下腔囊肿亦然。(二)外周性性早熟。 按不同病因分别处理,如各类肿瘤的手术治疗,先天性肾上腺皮质增生症予以皮质醇替代治疗等。
(男)2005年0~18岁儿童青少年身高百分位数值表年龄3rd10th 25th 50th75th90th97thSD占成人期身高比值初生~47.148.149.250.451.652.753.81.760.2920.5岁~64.065.466.868.470.071.573.02.400.3961岁~71.573.174.776.578.480.181.82.730.4431.5岁~76.978.780.682.784.886.788.73.130.4792岁~82.184.186.288.590.993.195.33.530.5122.5岁~86.488.690.893.395.998.2100.53.770.5403.0岁~89.791.994.296.899.4101.8104.13.850.5613.5岁~93.495.798.0100.6103.2105.7108.13.900.5834.0岁~96.799.1101.4104.1106.9109.3111.84.000.6034.5岁~100.0102.4104.9107.7110.5113.1115.74.170.6245.0岁~103.3105.8108.4111.3114.2116.9119.64.330.6445.5岁~106.4109.0111.7114.7117.7120.5123.34.500.6646岁~109.1111.8114.6117.7120.9123.7126.64.670.6827岁~114.6117.6120.6124.0127.4130.5133.75.070.7188岁~119.9123.1126.3130.0133.7137.1140.45.450.7539岁~124.6128.0131.4135.4139.3142.9146.55.830.78410岁~128.7132.3136.0140.2144.4148.2152.06.200.81211岁~132.9136.8140.8145.3149.9154.0158.16.680.84112岁~138.1142.5147.0151.9157.0161.5166.07.420.88013岁~145.0149.6154.3159.5164.8169.5174.27.780.92414岁~152.3156.7161.0165.9170.7175.1179.47.180.96115岁~157.5161.4165.4169.8174.2178.2182.06.530.98316岁~159.9163.6167.4171.6175.8179.5183.26.200.99417岁~160.9164.5168.2172.3176.4180.1183.76.080.99818~19岁161.3164.9168.6172.7176.7180.4183.96.031.000
年龄3rd10th 25th 50th75th90th97thSD占成人期身高比值初生~46.647.548.649.750.951.953.01.720.3090.5岁~62.563.965.266.868.469.871.22.320.4161岁~70.071.673.275.076.878.580.22.700.4671.5岁~76.077.779.581.583.685.587.43.030.5072岁~80.982.984.987.289.691.793.93.450.5432.5岁~85.287.489.692.194.697.099.33.730.5733.0岁~88.690.893.195.698.2100.5102.93.780.5953.5岁~92.494.696.899.4102.0104.4106.83.820.6194.0岁~95.898.1100.4103.1105.7108.2110.63.930.6424.5岁~99.2101.5104.0106.7109.5112.1114.74.120.6645.0岁~102.3104.8107.3110.2113.1115.7118.44.270.6865.5岁~105.4108.0110.6113.5116.5119.3122.04.420.7076岁~108.1110.8113.5116.6119.7122.5125.44.600.7267岁~113.3116.2119.2122.5125.9129.0132.14.980.7638岁~118.5121.6124.9128.5132.1135.4138.75.370.8009岁~123.3126.7130.2134.1138.0141.6145.15.800.83510岁~128.3132.1135.9140.1144.4148.2152.06.280.87211岁~134.2138.2142.2146.6151.1155.2159.26.630.91312岁~140.2144.1148.0152.4156.7160.7164.56.470.94913岁~145.0148.6152.2156.3160.3164.0167.66.020.97314岁~147.9151.3154.8158.6162.4165.9169.35.670.98815岁~149.5152.8156.1159.8163.5166.8170.15.480.99516岁~149.8153.1156.4160.1163.8167.1170.35.450.99717岁~150.1153.4156.7160.3164.0167.3170.55.420.99818~19岁150.4153.7157.0160.6164.2167.5170.75.371.000
人生长激素是脑垂体前叶分泌的一种激素,是体内最重要的促进生长的激素。儿童身高的增长主要是通过长骨骨干与骨骺之间的软骨板中的细胞分裂增殖实现的, 生长激素对软骨细胞的分裂增殖具有显著的促进作用。基因重组人生长激素应用于临床已有20多年的经验,在治疗小儿矮小症方面的疗效得到充分肯定,其治疗适应症也逐渐扩大,主要包括如下几种疾病: 一、生长激素缺乏症(GHD): GHD是由于各种原因导致垂体生长激素分泌不足所致的身材矮小,是儿童矮小症的主要原因,是生长激素的最佳适应症。治疗方法:开始剂量为每天0.1~0.14 IU /kg。开始治疗年龄宜早,生长激素对GHD患儿的促生长作用具有剂量依赖性,在治疗的前两年身高增长为10~12cm /年,随后生长速率减慢,一般保持在7~8 cm /年,若每3个月增长速度小于2cm,可增加剂量至每天0.15IU /kg。处于青春期,身材又较矮的GHD患儿可联合使用促性腺激素释放激素类似物,抑制骨龄加速,延长患儿骨骺闭合的时间,增加生长激素使用的时间,可取得更好的效果。生长激素的治疗效果与生长激素缺乏的程度、治疗开始的年龄、疗程、遗传身高及个体对生长激素的敏感性有关。 二、特发性矮小症 : 特发性矮小症是指因目前尚无可认知的原因引起的身材矮小,包括正常变异性矮小(包括家族性矮小、体质性生长青春期延迟) 、部分生长激素不敏感等。生长激素治疗方法: 特发性矮小症患儿由于自身并不缺乏生长激素,所以使用剂量较GHD患者大,一般为每天0.15 ~0.20IU /kg,治疗 3个月观察疗效,有效者继续治疗。青春期可联合使用促性腺激素释放激素类似物,延缓性激素对骨龄的加速,延长生长激素使用时间。 三、性早熟患者伴矮小症:性早熟患者常引起成年终身高低于遗传靶身高,尤其是矮小症患者。所以部分性早熟患者需要用生长激素治疗,剂量:每天0.15 ~0.20IU /kg,可与促性腺激素释放激素类似物联合使用,或单独使用。 四、Turner综合征: 又称先天性卵巢发育不全,是由于全部或部分体细胞中一条X染色体完全或部分缺失或结构畸变所致,部分患者伴有生长激素缺乏。生长激素治疗方法:生长激素治疗Turner综合征原则为及时诊断,尽早治疗,年龄越小疗效越好。伴有生长激素缺乏者使用剂量同生长激素缺乏症,不伴有生长激素缺乏者,需要剂量较大:每天0.15 ~0.20IU /kg,至骨龄12岁可加用雌激素治疗。 五、小于胎龄儿:是指出生体重或身长小于同胎龄正常小儿体重或身长的2SD以下。SGA在生后出现自发的追赶生长,多在3岁能赶上正常的同龄小儿,约10%的SGA 在儿童和成年后身高仍低于2SD,若3岁时仍矮小需要生长激素治疗。生长激素治疗方法:剂量为每天0.15~ 0.20IU/kg,追赶上正常同龄儿身高后停药观察,若停药后生长速度减慢,可继续使用生长激素治疗。 六、Prader-Williy综合征: Prader-Williy综合征是由于父源性印迹SNRPN基因和其他一些基因缺失引起的一种综合征,表现为身材矮小、重度肥胖、肌张力低、智力发育障碍和性腺发育不良。生长激素治疗方法:剂量为每天0.15~ 0.20IU/kg,观察疗效。 七、Noonan综合征:Noonan综合征是常染色体显性遗传病,特征为身材矮小、先天性心脏缺陷和特殊面容及体征,包括眼距宽,向下斜视,三角脸,颈蹼、短颈,低耳位,胸部畸形(胸廓狭窄或胸骨内陷) 。生长激素治疗方法:剂量为每天0.15~ 0.20IU/kg,观察疗效。 生长激素治疗过程中应随访监测,一般可3个月随访1次。项目包括测身高、体重、类胰岛素样生长因子-I和类胰岛素样生长因子结合蛋白-3、血糖及肝功能;甲状腺功能第一个疗程结束检测,若降低,按甲减治疗随访;骨龄检测,青春发育前期每年测一次,青春发育期每半年测1次。 停药时间:至青春发育后期生长激素治疗过程中身高增长率每年不足 2 cm,骨龄男孩16岁、女孩15岁时可以停药
Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology WorkshopP. Cohen, A. D. Rogol, C. L. Deal, P. Saenger, E. O. Reiter, J. L. Ross, S. D. Chernausek, M. O. Savage, J. M. Wit on behalf of the 2007 ISS Consensus Workshop participantsDepartment of Pediatric Endocrinology (P.C.), Mattel Children抯 Hospital at University of California, Los Angeles, Los Angeles, California 90095; Department of Pediatrics (A.D.R.), University of Virginia, and ODR Consulting, Charlottesville, Virginia 22911; Endocrinology Service (C.L.D.), Sainte-Justine Hospital, Montreal, Quebec, Canada H3T 1C5; Department of Pediatrics (P.S.), Albert Einstein College of Medicine, Bronx, New York 10467; Baystate Children抯 Hospital (E.O.R.), Tufts University School of Medicine, Springfield, Massachusetts 01199; Department of Pediatrics (J.L.R.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Department of Pediatrics (S.D.C.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104; Centre for Endocrinology (M.O.S.), the London School of Medicine and Dentistry, London E1 2AD, United Kingdom; and Department of Pediatrics (J.M.W.), Leiden University Medical Center, 2300 RC Leiden, The NetherlandsAddress all correspondence and requests for reprints to: Pinchas Cohen, M.D., Professor and Chief of Endocrinology, Mattel Children抯 Hospital at UCLA, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue MDCC 22-315, Los Angeles, California 90095-1752. E-mail: hassy@mednet.ucla.edu .AbstractObjective: Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). Participants: Participants were 32 invited leaders in the field.Evidence: Evidence was obtained by extensive literature review and from clinical experience.Consensus: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section.Conclusions: ISS is defined auxologically by a height below
Defining the Response to GH Treatment Short-term auxological features that suggest a successful first-year response to GH treatment in individual patients include a change in height SDS of more than 0.3–0.5, a first-year height velocity increment of more than 3 cm/yr, or a height velocity SDS of more than +1. Restoration to a more normal height during childhood is an important consideration. Mathematical models can be used to estimate responses to therapy with the selected dose (25). Biochemical features Serial IGF-I measurements during GH therapy are useful to assess efficacy, safety, and compliance and have been proposed as a tool for adjusting the GH dose. No other biochemical tests are routinely recommended in GH-treated ISS patients. Psychological features An important rationale for treatment with GH is the assumption that it will improve quality of life. Validated instruments sensitive to the specific domains that are affected in short children and that are easily administered in the clinic are needed but are not currently recommended as part of routine care. Interpretation of Outcome Measures Assessing the Success of GH Treatment Short-term outcome measures (i.e. <2 yr) must take into account the age, pubertal status, and degree of growth retardation of the individual patient. In most children with ISS, the change in height SDS will provide the best indicator of response, but height velocity, height velocity SDS, and the change in height velocity (centimeters per year or SDS) all have utility, and are sometimes superior, in assessing response when interpreted in light of the patient’s clinical situation. Long-term auxological parameters that define the success of therapy include adult height SDS, adult height SDS minus height SDS at start of GH, adult height minus predicted height, and adult height minus target height. Long-term psychosocial and metabolic outcomes should be evaluated in registries for these patients. Outcome of GH Therapy in Children with ISS The mean increase in adult height attributable to GH therapy (average duration of 4–7 yr) in children with ISS is 3.5–7.5 cm compared with historical controls (26, 27), with patients’ own pretreatment predicted adult heights (28), or with nontreatment control or placebo control groups (29, 30). Responses are highly variable and are dose dependent. Concern has been raised that higher GH doses (>53 g/kg·d) may advance the bone age and the onset of puberty (31), but this has not been found in other studies (32). Multiple factors affect the growth response to GH, many of which are unknown. Children who are younger or heavier, who receive higher GH doses, and who are shortest relative to target height have the best growth response. These factors account for approximately 40% of the variance in growth response. Adult height outcome is influenced negatively by age at start and positively by midparental height, height at start, bone age delay, and the first-year response to GH (23, 24). The utility of baseline and treatment-related biochemical data including IGF-I has not been validated in long-term studies, but 2-yr studies suggest that the rise in IGF-I correlates with short-term height gain (30). Monitoring for Efficacy and Safety in GH-Treated Children with ISS Children treated with GH should be monitored for height, weight, pubertal development, and adverse effects at 3- to 6-month intervals. Regular monitoring for scoliosis, tonsillar hypertrophy, papilledema, and slipped capital femoral epiphysis should be performed as part of the regular physical exam during follow-up visits. We recommend that after 1 yr, the response to therapy be assessed by calculating height velocity SDS as well as the change in height SDS. Pubertal stage should be assessed regularly, and bone age may be obtained periodically to reassess height prediction and for consideration of intervention to modify the tempo of puberty. IGF-I levels may be helpful in guiding GH dose adjustment, but the significance of abnormally elevated IGF-I levels remains unknown. Thus far, no instances of elevated blood glucose in GH-treated patients with ISS have been reported, but there is controversy regarding the need for routine monitoring of glucose metabolism. GH Treatment Adjustment Strategies Dosage is usually selected and adjusted by weight. If the growth response is considered inadequate, the dose may be increased. There are no definitive data concerning the long-term safety of doses higher than 50 g/kg·d in children with ISS. The upper limit of GH dosage used in other pediatric conditions is approximately 70 g/kg·d (28, 33), but the possibility of using such doses varies in terms of national health economics. In the United States, the current FDA-approved doses for GH in ISS are up to 0.3–0.37 mg/kg · wk (34). In the future, growth prediction models may improve GH dosing strategies. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. Recent studies on IGF-based dose adjustments in ISS demonstrated increased short-term growth when higher IGF targets were selected, but this strategy has not been validated in long-term studies with respect to safety, cost effectiveness, or adult height (31). Consideration of Adding Puberty Modulators If height prediction is below –2.0 SDS at the time of pubertal onset in either sex, the addition of GnRHa may be considered as discussed above (35, 36). Alternatively, in males, aromatase inhibitors may be an option (22). However, long-term efficacy and safety data are not available for either of these interventions. Also, the impact of delayed puberty on somatic and psychological development is not known. We do not recommend aromatase inhibitors for girls. Duration of GH Treatment There are two schools of thought about the duration of treatment. One is that treatment should stop when near adult height is achieved (height velocity <2 cm/yr and/or bone age >16 yr in boys and >14 yr in girls). Alternatively, therapy can be discontinued when height is in the normal adult range (above –2 SDS) or has reached another cutoff for the reference adult population (for example, in Australia, the 10th percentile; elsewhere, the 50th percentile). Stopping therapy is influenced by patient/family satisfaction with the result of therapy or ongoing cost-benefit analysis or when the child wants to stop for other reasons. Possible GH Side Effects The possible side effects in GH-treated children with ISS are similar to those previously reported in children receiving GH therapy for other indications (37). However, the frequency of adverse events is generally less (38). No long-term adverse effects have been documented. Posttreatment surveillance with focus on cancer prevalence and metabolic side effects is recommended, but the feasibility of such studies is unclear. Cost/Benefit Analysis The average ultimate height gain attributable to GH treatment in children with ISS, as well as the cost, are known (10,000–20,000 dollars/cm), but the short- and long-term benefits for the individual and society are unclear (26). It is presently not known whether, and how, a gain in height relates to change in quality of life. Therefore, GH treatment for children with ISS should be put in the context of the health budget for the specific country. At the current time, data demonstrating improved quality of life, better psychological health, etc. have not yet been collected in well-controlled studies. Therefore, recommendations for treatment that increases adult height should be balanced with the high cost of these therapies. The Definition of GH Nonresponsiveness The expected result of GH treatment in ISS is an increase in height SDS and height velocity resulting in increased adult height. Because there is a continuum of GH responses, the definition of nonresponsiveness is arbitrary. Suggested criteria for poor first-year response include height velocity SDS less than +1 or change in height SDS less than 0.3–0.5, depending on age. Emerging tools for the definition of GH treatment failures include prediction modeling and age- and gender-specific growth-response charts (39). If the growth response is lower and compliance is assured, among the options considered may be increasing the dose of GH. IGF-I values can be used to assess compliance and sensitivity to GH. If after 1–2 yr and higher doses of GH, the growth rate is still inadequate, GH treatment should be stopped and alternative therapies could be entertained. Future Studies Future studies on the management of children with ISS should involve three major areas. The first is improvement in diagnostic tools to categorize the different subpopulations who fall within the definition of ISS and their response to therapy. These would include molecular genetics, proteomics, and pharmacogenomics, better measures of GH and IGF-I sensitivity, and improved prediction models. The second area should involve psychosocial instruments, interventions, and outcomes. A third area is the conduct of well-controlled studies on the use of adjunctive pharmacological interventions such as the combination of GH and GnRHa, aromatase inhibitors, or IGF-I. Conclusions ISS represents a significant clinical entity within the pediatric endocrinology practice, and multiple therapeutic interventions may be considered for these patients after appropriate evaluation has been conducted. Further clinical research and development is warranted to optimize the management of these children and to ensure that treatments are safe and beneficial. Acknowledgments Consensus Workshop participants include David Allen, University of Wisconsin School of Medicine and Public Health, Madison, WI; Ivo Arnhold, Universidade de Sao Paulo, Sao Paulo, Brazil; Peter Bang, Karolinska Institute, Stockholm, Sweden; Fernando Cassorla, University of Chile, Santiago, Chile; Stefano Cianfarani, Tor Vergata University, Rome, Italy; Steven Chernausek, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Jens Christiansen, Aarhus University Hospital, Aarhus, Denmark; Pinchas Cohen, UCLA, Los Angeles, CA; Leona Cuttler, Case Western Reserve University, Cleveland, OH; Paul Czernichow, Necker Enfants Malades University Hospital, Paris, France; Peter Davies, University of Queensland, Herston, Australia; Université de Montréal, Montreal, Canada; Yukihiro Hasegawa, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan; Chris Kelnar, University of Edinburgh, Scotland UK; Sandro Loche, Ospedale Regionale per le Microcitemie, Cagliari, Italy; Louis Low, University of Hong Kong, Hong Kong, China; Nelly Mauras, Nemours Children’s Clinic, Jacksonville, FL; Meinolf Noeker, University of Bonn, Bonn, Germany; John Parks, Emory University School of Medicine, Atlanta, GA; Moshe Phillip, Schneider Children’s Medical Center of Israel, Tel-Aviv University, Petah Tikva, Israel; Michael Ranke, University Hospital for Children and Adolescents, Tubingen, Germany; Sally Radovick, Johns Hopkins University School of Medicine, Baltimore, MD; Edward Reiter, Tufts University School of Medicine, Springfield, MA; Alan Rogol, University of Virginia, Charlottesville, VA; Stephen Rosenthal, UCSF, San Francisco, CA; Judy Ross, Thomas Jefferson University, Philadelphia, PA; Paul Saenger, Albert Einstein College of Medicine, Bronx, NY; David Sandberg, University of Michigan, Ann Arbor, MI; Martin Savage, London School of Medicine and Dentistry, London, UK; Lars Savendahl, Karolinska Institutet, Stockholm, Sweden; Jan-Maarten Wit, Leiden University Medical Center, Leiden, The Netherlands; and Susumu Yokoya, National Center for Child Health and Development, Tokyo, Japan. Industry nonvoting participants included Eli Lilly and Co.; Barbara Lippe, Genentech; Ann-Marie Kappelgaard, Novo Nordisk A/S; Mireille Bonnemaire, Ipsen, Ltd.; George Bright, Tercica, Inc.; and Jose Cara, Pfizer Global Pharmaceuticals. Footnotes The Consensus Workshop was organized and supported by the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society of Pediatric Endocrinology and supported in part by unrestricted education grants from Eli Lilly and Co., Ferring, Genentech, Ipsen, JCR Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, and Tercica. Endorsements: The Consensus document was endorsed by the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society (LWPES), the European Society of Pediatric Endocrinology (ESPE), the Latin American Society of Pediatric Endocrinology (SLEP), the Japanese Society of Pediatric Endocrinology (JSPE), the Canadian Pediatric Endocrine Group (CPEG), the Asia Pacific Pediatric Endocrine Society (APPES), and the Australasian Pediatric Endocrine Group (APEG). Disclosure Statement: P.C. is a consultant to Tercica and Novo Nordisk and received grant support from Pfizer, Genentech, and Eli Lilly and Co. A.D.R. is a consultant to Tercica, Novo Nordisk, Genentech, Serono, and Pfizer. C.L.D. is a consultant to Serono and Eli Lilly, and Co. and a speaker for Novo Nordisk. P.S. is a consultant to Sandoz. E.O.R. is a consultant to Pfizer and a speaker for Genentech. J.L.R. is a consultant to Eli Lilly and Co. S.D.C. is a consultant for Tercica. M.O.S. is a consultant to Ipsen. J.M.W. is a consultant to Ipsen, Eli Lilly, and Tercica and received grant support from Pfizer, Novo Nordisk, Ferring, and Ipsen.
由于家长和青少年对身高广泛关注,各种“增高”产品应运而生。目前市面上所售的“增高”口服药及保健品名目繁多,但其主要成分不外乎几大类:①主要成分为赖氨酸等加钙剂和多种维生素,对促进生长有一定辅助作用,但对明显生长落后者疗效不明显。②主要成分为蛋白同化剂类固醇,短期内有一定促生长效果,但促进骨骺过早闭合,副作用明显,对最终身高不利。③主要成分为雄激素,短期内有一定促生长效果,但使骨骺迅速闭合,身高增长立即停止,并可能出现女性男性化,男性性早熟,最终身材矮小。④主要成分为中草药,可改善食欲,帮助消化吸收,但疗效有限。且多种产品可能添加固醇类激素,可致性早熟并使骨骺提前闭合,影响最终身高。 众多产品往往成本低廉而价格昂贵,疗效甚微,还可能造成严重不良后果。 在门诊经常遇到有家长反映孩子服用多个疗程的“增高”药后未见长高,经检查诊断为生长激素完全或部分缺乏,显然仅补充一些氨基酸、钙剂和维生素等不可能有显著疗效。而另一些家长反映孩子服药后短期内有较明显长高,但很快生长停滞并出现性发育征象。检查后往往发现孩子骨龄超前甚至已经闭合,失去了干预治疗的时机。家长在日常生活中要注意定期测量孩子的身高并监测年生长速率,及时发现异常。如身高明显落后于同龄儿童或每年增长低于相应年龄阶段的正常速率,就应到正规医院咨询或就诊。 民间所谓在青春发育期吃“小公鸡”等促进长高的说法并无科学依据。其机理大概是认为“小公鸡”是生长发育期的鸡,含性激素水平比较高,认为可能对孩子身高有帮助。其实青春期的孩子性激素水平本来就高,如过多地摄取含性激素类的食品,一是容易引起内分泌失调,出现女孩长胡须、男孩长青春痘等症状,二是容易引起骨骺过早闭合,对孩子最终身高不利。青春期的孩子应该均衡摄取营养,保证充足的蛋白质食物如鸡蛋、鱼、牛奶、瘦肉等以供身体快速增长之需要,切忌盲目减肥节食,影响生长发育。
孩子长高的潜力有多大 遗传在很大程度上决定了孩子的生长潜力,但是孩子的生长受到很多因素的综合影响。如果孩子双亲身高正常、生长发育的条件都比较好,那么孩子的生长发育就会比较满意;相反如果孩子的双亲身材较矮,家长又不注意孩子后天的营养摄取,运动锻炼,那么孩子的身高也不会理想。有一个公式可以大概计算孩子的成年期身高(遗传靶身高)范围:男孩为父母平均身高加6.5厘米,女孩为父母平均身高减6.5厘米,所得数值在±5厘米即为该儿童成年后的身高范围。遗传性靶身高有较大的波动范围,后天的营养、睡眠、运动和疾病等多种因素会对最终身高产生很大的影响。 如何充分发挥孩子的生长潜力,虽然遗传在很大程度上决定了孩子的生长潜力,但最终身高受诸多因素影响。充足的营养是生长发育的基本保障,蛋白质是骨骼与肌肉生长的物质来源,同时又能促进生长激素的分泌,是儿童生长发育的最基本要素。因此,在儿童饮食的调剂中,要给予富含蛋白质的食物,如蛋类、肉类、鱼类、豆制品类和乳制品类。 适当强度的运动能直接促进生长激素的分泌,同时身体充分的运动能增进孩子的食欲,带给孩子健康的睡眠,对长高有帮助。有益于长高的运动有慢跑、跳绳、跳舞、打篮球、打排球、游泳等纵向压力的运动,因为骨骼的发育一定程度上来自纵向的压力,而过强的压力如举重等会阻止骨骼纵向生长,孩子应避免做这样的运动。 由于生长激素的分泌一般在夜间孩子熟睡后1小时左右达最高峰,充足的睡眠能促进生长激素的分泌,所以家长要督促孩子每天晚上8、9点钟入睡,保证睡眠充分。 此外,身体的发育受自然环境、社会环境与家庭环境的影响,特别是低年龄的儿童受家庭环境影响尤其明显。父母的关爱有助于孩子的长高,孩子如果在不和谐的家庭中长大,得不到父母的关爱往往影响身体长高,因此,一定要为孩子营造有益身心健康、关爱有加的生长环境。 身高的增长速度并不是均匀的。人的一生身高增长要经历两个快速增长时期,即婴幼儿期(0-3岁)及青春期。青春期由于性激素的协同作用,孩子身高会出现“窜个”的现象,但也由于性激素的作用孩子的骨骺会迅速闭合,身高不再继续增长。男孩青春期开始一般为12-13岁,年生长速率可达7-10厘米,平均身高可增长25-28厘米;女孩青春期开始一般为10-11岁,年生长速率可达6-9厘米,平均身高可增长23-25厘米。婴幼儿期和青春期为身高增长的重要时期,应予以高度重视。