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ACRP

Asian Case Reports in Pediatrics

2328-045X

Scientific Research Publishing

10.12677/ACRP.2013.14015

ACRP-12455

ACRP20130400000_75283876.pdf

医药卫生

儿童Prader-Willi综合征合并扩张性心肌病一例 A Case of Prader-Willi Syndrome with Dilated Cardiomyopathy

刘

栋

² ¹ 赵

映敏

² ¹

靖江市人民医院儿科

null

09 10 2013

01 04 57 59 Jul. 8th, 2013 Jul. 29th, 2013 Aug. 5th, 2013

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Prader-Willi 综合征是由于 15 号染色体长臂特异区基因缺失或母源二倍体所致，其共同的临床表现为新生儿期肌张力低下，儿童期肥胖，智力低下，青春期无性发育，身材矮小。本文报道儿童 Prader-Willi 综合征合并扩张性心肌病一例，并探讨 Prader-Willi 综合征的临床表现及遗传学特征、治疗方案，及与扩张性心肌病之间的关联。 Prader-Willi syndrome (PWS) is a disorder caused by a deletion or disruption of genes in the proximal long arm of chromosome 15 or by maternal disomy in the proximal long arm of chromosome 15. Commonly associated characteristics of this disorder include diminished fetal activity, hypotonia, obesity, mental retardation, short stature, hypogonadism, and small hands and feet. We report a case of Prader-Willi syndrome with dilated cardiomyopathy, and review its Clinical manifestations, genetic characteristics and treatment method, then analysis the relation with the di- lated cardiomyopathy.

Prader-Willi综合征；基因组印记；基因缺失；生长激素；扩张性心肌病, Prader-Willi Syndrome; Genomic Imprinting; Gene Deletion; Growth Hormone; Dilated Cardiomyopathy

1. 引言

病例报道：患儿男，8岁6月，因“全身浮肿一周、气促四天”入院。有进行性肥胖病史四年。查体：身高120 cm，体重48 kg，血压180/120 mmHg，血氧饱和度75%，神志清，精神欠佳，向心性肥胖，手足小，全身重度凹陷性水肿，呼吸急促，口唇紫绀，双肺呼吸音粗，呼吸45/分，无啰音，心率120次/分，律齐，心音低，无明显杂音，蛙状腹，肝脾触诊不佳，移动浊音阳性，下肢重度水肿，神经系统无异常。个人史：第一胎第一产，足月顺产，出生体重2300 g，否认窒息抢救史，5个月抬头，9个月认人，12个月会坐，两岁能独走。平时食量大，活动量少。家族史：父母均体健，否认遗传性家族性疾病。辅助检查：心脏彩超：左室增大，中度肺动脉高压，LVEF35%。胸片：心影增大，胸椎侧弯。诊断：1) 扩张性心肌病并心功能不全，2) 重度肥胖，3) 胸椎侧弯。入院后予头孢曲松抗感染、速尿利尿、西地兰强心、卡托普利、缬沙坦氢氯噻嗪、安体舒通降压治疗，患儿发绀、气促逐渐缓解，血压降至150/100 mmHg，水肿消退，予出院，带药缬沙坦氢氯噻嗪、安体舒通、压士达、地高辛，随访。出院后行染色体分析：检测到15q11~13的父源片段丢失。

2. 讨论

Prader-Willi综合征(PWS)最早由Prader于1956年报道而得名，是因15q11~13的父源片段的丢失而导致的染色体微缺失综合征^[1,2]。

2.1. 临床表现

PWS是一种多系统异常的疾病，不同生长发育阶段有相应的临床表现：1) 胎儿及新生儿期：宫内发育迟缓，平均出生体重低于2500 g，肌张力低，喂养困难，男孩常伴有隐睾症。2) 婴幼儿及青春前期：6个月大后喂养困难逐渐改善，特殊面容有窄脸、杏仁眼、三角嘴，手足小，身材矮小，饮食过量，过度肥胖，智力低下，易怒，痛域高，可伴有斜视、眼球震颤及脊柱侧弯。3) 青春期：无明显第二性征发育，下丘脑性发育不良，常继发非胰岛素依赖型糖尿病、睡眠呼吸暂停等^{[

3
]}。死因多继发于糖尿病、心力衰竭、急性睡眠呼吸暂停。

2.2. 遗传特征与基因分析

PWS大多为15q11~13的父源片段丢失，母亲基因不表达(70%)。少部分为单亲二体，即二条15号染色体均来自母亲，系父源缺失代之以母源复制(27%) ^{[

4
]}。极少数为遗传印记突变(3%)，系SNRPN基因甲基化异常所致^{[

5
]}。SNRPN基因是位于15q12的一个遗传印迹中心，约25 kb，有10个外显子，只有父源15号染色体上的SNRPN基因有活性。正常情况下SNRPN基因的第7内含子只有在父源染色体被甲基化，而其CpG岛在母源染色体被甲基化。这种甲基化起着重要的基因修饰作用，若甲基化位点发生变化就会产生遗传印迹突变，造成父源基因不表达，甲基化PCR(MSPCR)可以帮助诊断。也有研究表明15q12的缺失与PWS糖尿病的发作有关^{[

6
]}。目前高分辨染色体分析和荧光原位杂交(FISH)可以诊断15q11~13的父源片段丢失及SNRPN基因的微小缺失。

2.3. 治疗

2000年注射用生长激素被FDA正式批准应用于PWS的长期治疗，已取得良好疗效。PWS患者存在下丘脑性生长激素(GH)缺乏，因而GH治疗可改善患者的身体脂肪组成、改善肌肉强度和改善骨密度，长期应用可改善终身高。最近有研究发现^{[

7
]}GH还可改善神经认知发育，应用GH期间患者的反应速度和适应性都得到了明显改善，但是停用后机体结构和社会交往能力会有所下降。配合以饮食控制及物理康复训练可取得较好效果^[8-10]。此外应用GH治疗过程中药高度警惕有无呼吸系统疾病，因为PWS的猝死多与呼吸系统感染及呼吸道梗阻所致的呼吸衰竭有关，要注意预防感染，保持呼吸道通畅，对有呼吸道狭窄、扁桃体增殖腺肥大和打鼾的患儿要密切监控，夜间可给予适当的低流量吸氧。

2.4. 与扩张性心肌病的关系

扩张性心肌病(dilated cardiomyopathy DCM)是以心脏扩大，心肌收缩力减弱为主要特征的原因不明的心肌疾病。目前尚无特异性治疗方法，预后较差，常用药物有血管紧张素转换酶抑制剂、β受体阻滞剂及利尿剂等，主要为针对症状和并发症的治疗。近年来儿童DCM发病率有增高趋势，主要病因有自身免疫、病毒感染、遗传因素。本例PWS患儿合并有DCM，笔者分析可能原因如下：1) PWS患儿生长激素水平低：有研究表明，GH缺乏可引起DCM，DCM患者血中GH水平、IGF-1水平降低^{[

11
]}。GH和IGF-1在心血管系统的生理中起着重要作用，其水平上升可通过增加心肌细胞的基因表达而使心肌细胞增生，减少室壁张力，增加心脏收缩力，并能改善心脏的后负荷^{[

12
]}。GH还可通过减少TNF和增加T₂辅助细胞等抗炎因子减少细胞凋亡，逆转心力衰竭发展。而GH和IGF-1水平下降会增加儿茶酚胺的敏感性并使外周血管阻力增加^{[

13
]}。2) PWS患儿易合并阻塞性睡眠呼吸暂停综合征：阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea hypopnea syndrome, OSAHS)的主要病理生理改变是慢性间歇缺氧，睡眠结构异常，在此基础上导致血压、心率的剧烈波动。OSAHS可通过氧化应激反应损害血管内皮功能，引起血管重构，引发微灶性心肌梗死，进而导致心室重构、心功能下降^{[

14
]}。目前扩张性心肌病未有确切病因，其与PWS的关系有待进一步研究。

参考文献 (References)

[ 1 ] M. Gunay-Aygun, S. Schwartz, S. Heeer, et al. The changing purpose of Prader-Willi syndrome, cilinical diagnostic criteria and propose revised criteria. Pediatrics, 2001, 108(5): E92.

[ 2 ] R. D. Nicholls, S. Saitoh and B. Horsthemke. Imprinting in Prader-Willi and Angelman syndrome. Trends in Genetics, 1998, 14(5): 194-200.

[ 3 ] V. A. Holm, S. B. Cassidy, M. G. Butler, et al. Prader-Willi syndrome: Consensus diagnostic. Pediatrics, 1993, 91(2): 398-402.

[ 4 ] H. Soejima, J. Wagstaff. Imprinting centers, chromatin sturcture, and disease. Journal of Cellular Biochemistry, 2005, 95(2): 226- 233.

[ 5 ] L. Keder, M. G. Bulter. The genetics of Prader-Willi syndrome: An explanation for the rest of US. 2000. http://www.pwsausa.org/syndrome/Genetics_of_PWS.htm.

[ 6 ] R. Bassali, W. H. Hoffman, H. Chen, et al. Hyperlipidemia, insulin-dependent diabetes mellitus, and rapidly progressive diabetic retinopathy and nephropathy in Prader-Willi syndrome with del(15)(q11.2q13). American Journal of Medical Genetics, 1997, 71(3): 267-70.

[ 7 ] C. Höybye, A. Hilding, C. Marcus, et al. Growth hormone induced lipolysis during shortand long-term administration in adult Prader-Willi patients. Growth Hormone & IGF Research, 2005, 15(6): 411-415.

[ 8 ] A. L. Carrel, S. E. Myers, B. Y. Whitman, et al. Growth hormone mproves body compostion, fat utilization, physical strenth and agility, and growth inPrader-Willi syndrome: A controlled study. Journal of Pediatrics, 1999, 134(2): 215-221.

[ 9 ] S. E. Myers, A. L. Carrel, B. Y. Whitman, et al. Suatained benefit after 2 years of growth hormone on body compostion, fat utilization, physical strength and agility, and frowth in PraderWilli syndrome. Journal of Pediatrics, 2000, 137(1): 42-49.

[ 10 ] A. L. Carrel, S. E. Myers, B. Y. Whitman, et al. Sustained benefits of growth hormone on body compostion, fat utlization, physical strength and agility, and growth in Prader-Willi syndrome are dose-dependent. Journal of Pediatric Endocrinology & Metabolism, 2001, 14(8): 1097-1105.

[ 11 ] B. L. Silverman, J. R. Friedlander. Is growth hormone good for the heart? Journal of Pediatrics, 1997, 131: S70-S74.

[ 12 ] A. Colao, P. Marzullo, C. Di Somma, et al. Growth hormone and the heart. Clinical Endocrinology, 2001, 54(2): 137-154.

[ 13 ] A. Giustina, E. Boni, G. Romanelli, et al. Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide. American Journal of Cardiology, 1995, 75(15): 1042-1047.

[ 14 ] M. E. Otto, M. Belohlavek, A. Romero-Corral, et al. Comparison of cardiac structural and functional changes in obese otherwise healthy adults with versus without obstructive sleep apnea. American Journal of Cardiology, 2007, 99(9): 1298-1302.

References 1

M. Gunay-Aygun, S. Schwartz, S. Heeer, et al. The changing purpose of Prader-Willi syndrome, cilinical diagnostic criteria and propose revised criteria. Pediatrics, 2001, 108(5): E92.

R. D. Nicholls, S. Saitoh and B. Horsthemke. Imprinting in Prader-Willi and Angelman syndrome. Trends in Genetics, 1998, 14(5): 194-200.

V. A. Holm, S. B. Cassidy, M. G. Butler, et al. Prader-Willi syn- drome: Consensus diagnostic. Pediatrics, 1993, 91(2): 398-402.

H. Soejima, J. Wagstaff. Imprinting centers, chromatin sturcture, and disease. Journal of Cellular Biochemistry, 2005, 95(2): 226- 233.

L. Keder, M. G. Bulter. The genetics of Prader-Willi syndrome: An explanation for the rest of US. 2000. http://www.pwsausa.org/syndrome/Genetics_of_PWS.htm.

R. Bassali, W. H. Hoffman, H. Chen, et al. Hyperlipidemia, insu-lin-dependent diabetes mellitus, and rapidly progressive diabetic retinopathy and nephropathy in Prader-Willi syndrome with del(15)(q11.2q13). American Journal of Medical Genetics, 1997, 71(3): 267-70.

C. Höybye, A. Hilding, C. Marcus, et al. Growth hormone in- duced lipolysis during short- and long-term administration in adult Prader-Willi patients. Growth Hormone & IGF Research, 2005, 15(6): 411-415.

A. L. Carrel, S. E. Myers, B. Y. Whitman, et al. Growth hor- mone mproves body compostion, fat utilization, physical strenth and agility, and growth inPrader-Willi syndrome: A controlled study. Journal of Pediatrics, 1999, 134(2): 215-221.

S. E. Myers, A. L. Carrel, B. Y. Whitman, et al. Suatained bene- fit after 2 years of growth hormone on body compostion, fat utilization, physical strength and agility, and frowth in Prader- Willi syndrome. Journal of Pediatrics, 2000, 137(1): 42-49.

A. L. Carrel, S. E. Myers, B. Y. Whitman, et al. Sustained bene- fits of growth hormone on body compostion, fat utlization, phy- sical strength and agility, and growth in Prader-Willi syndrome are dose-dependent. Journal of Pediatric Endocrinology & Me- tabolism, 2001, 14(8): 1097-1105.

B. L. Silverman, J. R. Friedlander. Is growth hormone good for the heart? Journal of Pediatrics, 1997, 131: S70-S74.

A. Colao, P. Marzullo, C. Di Somma, et al. Growth hormone and the heart. Clinical Endocrinology, 2001, 54(2): 137-154.

A. Giustina, E. Boni, G. Romanelli, et al. Cardiopulmonary per- formance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide. American Journal of Cardiology, 1995, 75(15): 1042-1047.

M. E. Otto, M. Belohlavek, A. Romero-Corral, et al. Compari- son of cardiac structural and functional changes in obese other- wise healthy adults with versus without obstructive sleep apnea. American Journal of Cardiology, 2007, 99(9): 1298-1302.