ACRP  >> Vol. 7 No. 1 (February 2019)

    以肺动脉高压为首发症状的先天性中枢性低通气综合征一例
    Congenital Central Hypoventilation Syndrome with Initial Symptom of Pulmonary Hypertension: Case Report and Literature Review

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作者:  

单光颂,王本臻,纪志娴,李自普:青岛市妇女儿童医院心脏中心,山东 青岛;
李 晶,曲妮燕:青岛市妇女儿童医院重症医学中心,山东 青岛

关键词:
先天性中枢性低通气综合征PHOX2B基因无创双水平正压通气Congenital Central Hypoventilation Syndrome PHOX2B Noninvasive Bi-Level Positive Airway Pressure

摘要:

目的:提高对先天性中枢性低通气综合征(CCHS)临床表现、诊断及治疗的认识。方法:分析总结1例于我院住院治疗的伴有肺动脉高压的CCHS患儿的临床资料,并进行文献复习。结果:患儿初次入院以肺动脉高压为首发症状,入院时面罩吸氧下氧饱和度难以维持正常,遂予机械通气,病情平稳后撤机出院,但患儿短时间内多次因呼吸道感染、低氧血症入院治疗,期间存在呼吸机撤机困难及夜间自主呼吸差等症状,除外肺部原发病以及神经肌肉功能障碍等疾病后,完善全外显子基因检测,PHOX2B基因存在变异,结合患儿临床表现及基因检测结果诊断为先天性中枢性低通气综合征,经无创正压通气及支持治疗后,患儿肺动脉压力下降明显,氧和可维持基本稳定,生活质量明显改善。结论:CCHS患儿经无创双水平正压通气治疗后可显著改善预后。

Objective: To describe the clinical characteristics of congenital central hypoventilation syndrome (CCHS) with pulmonary hypertension. Methods: We retrospectively analyzed a patient with CCHS who presented with pulmonary hypertension and review of the literature. Results: The patient presented with pulmonary hypertension at the time of first hospitalization, and echocardiogram revealed enlarged right ventricle and atrium, in spite of activity measures including mechanical ventilation and supportive treatment, the patient had persistent cyanosis and dyspnea, the patient proceeded with genetic testing. A genetic research was performed by polymerase chain reaction for CCHS screening, which showed the mutated allele of PHOX2B gene, confirming the diagnosis. After non-invasive positive pressure ventilation treatment, the patient thrived with normal growth and development. Conclusion: The present paper illustrates that the most effective and common method of treatment for CCHS is non-invasive bi-level positive pressure ventilation.

1. 引言

先天性中枢性低通气综合征(Congenital central hypoventilation syndrome, CCHS)是一种罕见的染色体疾病,该病典型的临床表现是患儿清醒状态时有足够的自主通气,而在睡眠时会出现通气不足,引起高碳酸血症和/或低氧血症等,目前无创正压通气是治疗该病的有效手段之一,本文报道的是一例以肺动脉高压为首发症状的先天性中枢性低通气综合征患儿,对其进行回顾分析,进一步让临床医师提高对先天性中枢性低通气综合征临床表现、诊断及治疗的认识。

2. 病例报道

患儿男,7月5天,因“双下肢水肿10天,双眼睑浮肿伴腹胀5天,加重1天”入院。患儿系第四胎第三产,足月剖宫产,出生体质量4.55 kg,母孕期体健,无家族性遗传病史。生后曾因“口周发绀4小时”住院治疗10天,病情好转后出院。入院查体:体温36.1℃,心率118次/分,呼吸30次/分,血压111/74 mmHg (14.8/9.7 kPa),体重10 kg;面罩吸氧下氧饱和度维持在92%左右;神志清,精神反应可,呼吸平稳;全身皮肤粘膜无黄染及出血点,头颅无畸形,前囟未闭,双眼睑水肿,咽略充血。双侧呼吸动度一致,两肺呼吸音粗,未闻及干湿性啰音;心前区无隆起,心尖搏动无弥散,心音有力,律整,各瓣膜听诊未闻及杂音,肺动脉区第二心音稍亢进。腹膨隆,触软,肝右肋下4.5 cm,脾左肋下未触及,腹壁静脉略显露;脊柱四肢无畸形,关节活动无受限,双下肢水肿,肢端暖。入院前查尿常规示尿隐血2+,尿蛋白1+;血常规示白细胞9.48 × 109 /L (参考范围4~10 × 109/L),血红蛋白139 g/L (参考范围 110~170 g/L),血小板248 × 109/L (参考范围100~300 × 109/L),中性粒细胞39.6% (参考范围50%~70%);C反应蛋白3.72 mg/L (参考范围0~8 mg/L)。入院后复查尿常规(晨尿)示尿隐血2+,尿蛋白1+,比重1.004,红细胞管型27.1/uL。腹部超声示肝脏肿大,胆囊壁增厚,右肾积水;超声心动图示右心房30 × 23 mm,左室射血分数65%,肺动脉压力75 mmHg (图2(B)、图2(C))。入院后予禁食、限制液速,地高辛强心,呋塞米减轻水肿等治疗;多次复查静脉血气分析示二氧化碳分压波动于38~88 mmHg之间,氧分压波动于53~169 mmHg间。床旁胸部正位片示心影明显增大,心胸比约0.73,双肺纹理增多、模糊(图2(A))。入院7小时患儿面罩吸氧下氧饱和度降至60%,面色发绀,心率降至80次/分,复苏囊加压给氧,氧饱和度缓慢回升90%以上,心率升至100次/分,接面罩吸氧后氧饱和度再次快速下降至70%左右。行机械通气(PRVC模式),上机后心电监护示心率100次/分,氧饱和度95%以上,自主呼吸活跃,后渐降呼吸机参数后撤机。撤机后鼻导管吸氧下氧饱和度可维持在95%左右,但离氧不耐受。进一步完善检查,脑利钠肽前体为12,301 pg/ml,免疫球蛋白组合、降钙素原、血沉及抗“Ο”滴度正常;ANCA、抗心磷脂抗体、抗核抗体、自免全套均无异常;胸部CT示双侧肺炎并右肺下叶肺膨胀不全,心影增大,心包积液,右侧胸腔少量积液,且扫及层面可见腹水。再次复查超声心动图示右房右室增大,左室射血分数66%,PASP 52 mmHg。患儿病情平稳后出院随访治疗。此后因“呼吸道感染、低氧血症”反复入院3次。出院3月后,再次因“咳嗽1周,喘憋、青紫半天”入院,入院当日突现抽搐,面罩吸氧吸下氧饱和度维持在85%左右,血气示氧分压74 mmHg、二氧化碳分压51 mmHg,予机械通气,监测血气很快正常,自主呼吸活跃后撤机。撤机6小时后患儿鼻导管吸氧下在睡眠中出现面色发绀,氧饱和度70%~80%,再次上机;3天后患儿反应佳,再次撤机,如此反复3次。医学全外显子基因检测示PHOX2B基因3号外显子766~780存在杂合突变,导致多聚丙氨酸序列A256-A260存在异常重复(p.A256_A260dup),基因型为20/25 (图1)。结合患儿临床表现及基因检测结果确诊为先天性中枢性低通气综合征。患儿病情平稳后撤机,院外给予睡眠时无创双水平正压通气,强心、利尿及降低肺动脉压力等治疗,定期随访。给予简易呼吸机治疗后半年复查超声心动图示房室腔内径基本恢复正常,肺动脉压力下降至36 mmHg,胸片示心胸比恢复正常(图3);目前仍密切随访中。

Figure 1. (A) Sequencing map of children; (B) Gene test results in children with PHOX2B gene; C.766_780dup (p.A256_A260dup) heterozygous mutation, the type of mutation is the expansion mutation of alanine repeat sequence coding for exon PHOX2B, resulting in 20 alanine repeats of PHOX2B amplified to 25 repeats, genotype 20/25

图1. (A) 患儿一代测序图;(B) 患儿基因检测结果提示PHOX2B基因;c.766_780dup (p.A256_A260dup)杂合变异,突变类型为PHOX2B外显子编码丙氨酸重复序列扩展突变,导致PHOX2B的20个丙氨酸重复扩增到25个重复,基因型为20/25

Figure 2. (A) The chest X-ray cardiogram showed a marked increase with a cardiothoracic ratio of about 0.71, and the texture of both lungs was increased and blurred; (B) Echocardiogram showed tricuspid regurgitation and estimated pulmonary artery pressure of 77 mmHg; (C) Four-chamber echocardiographic view of the patient indicates right atrium and right ventricle enlargement

图2. (A) 患儿入院胸片心影明显增大,心胸比约0.71;双肺纹理增多、模糊;(B) 超声心动图提示存在三尖瓣反流,估测肺动脉压力77 mmHg;(C) 患儿超声心动图四腔心切面提示右房右室大

Figure 3. (A) Chest radiographs of children after treatment indicated a cardiothoracic ratio of about 0.55; (B) Echocardiogram suggests that pulmonary artery pressure is estimated at 36 mmHg; (C) Four-chamber echocardiographic view of the patient indicates that the size of the atrioventricular cavity is basically normal and the right ventricular wall is hypertrophic

图3. (A) 治疗后患儿复查胸片提示心胸比约0.55;(B) 超声心动图提示估测肺动脉压力36 mmHg;(C) 患儿超声心动图四腔心切面提示房室腔大小基本恢复正常,右室壁心肌肥厚

3. 讨论

先天性中枢性低通气综合征是一种少见的常染色体显性遗传病,该病的主要致病基因为paired-like homeobox gene 2B (PHOX2B) [1] [2] ,但RET、HASHI、GDNF、EDN3等基因突变也可导致CCHS的发生 [3] 。CCHS的发病机制可能为二氧化碳对中枢化学感受器的调节障碍,造成肺通气减少,从而导致高碳酸血症、低氧血症及一系列临床症状的综合征。CCHS好发于新生儿期,少数患者为儿童及成人起病,典型临床特点为清醒时通气良好,睡眠时通气不足,呈现慢性呼吸衰竭,而心、肺功能正常。该病在国内报道较少 [4] ,但预后差,多数患儿放弃治疗或死亡 [5] [6] [7] ;国外报道部分患儿通过无创双水平正压通气治疗,其存活时间、远期预后明显高于其他方式治疗的患者 [8] 。

CCHS目前采用的诊断标准为 [9] :1) 持续存在的睡眠状态通气不足及高碳酸血症(PaCO2 > 60 mmHg);2) 症状在1年内出现;3) 除外可导致肺通气不足的肺部原发病或神经肌肉功能障碍;4) 无心脏原发病的表现。在疾病早期多数患儿临床表现不典型,部分患儿以便秘、吞咽障碍、低血糖、癫痫发作等 [10] [11] [12] 呼吸系统以外的症状就诊。本例患儿就诊时存在多汗、水肿、肺动脉高压等临床表现,其超声心动图示除肺动脉压力增加外并无心脏结构性异常,考虑由低氧血症和通气不足引起 [13] [14] 。CCHS患儿的首发症状多变,极易误诊;当临床遇到表现为严重自主呼吸困难,特别是睡眠时高碳酸血症和低氧血症的患儿时应警惕该病。

CCHS具有典型的家族聚集性,PHOX2B基因编码的蛋白含两条丙氨酸重复序列,长的一条由20个丙氨酸重复序列组成,基因型为20/20;当该基因突变时可导致丙氨酸重复扩展或丙氨酸错义、无义和移码突变,其中丙氨酸重复扩展突变最常见的基因型为20/25、20/26和20/27 [15] ;本例患儿基因型为20/25为常见突变类型之一。国外已将PHOX2B基因的检测作为确诊CCHS的诊断依据之一 [1] [16] ,临床高度怀疑该病时应积极基因检测。继发型低通气综合征可见于创伤、肿瘤、先天性中枢神经系统畸形(如Chiari畸形)、肌营养不良、膈肌麻痹等,临床需借助相应辅助检查予以仔细鉴别,但继发型低通气综合征在原发疾病好转后通气障碍可明显改善。

CCHS由常染色体基因突变所致,故其临床表现、治疗均存在异质性,部分患者通过药物治疗疗效欠佳,需经呼吸支持和膈肌起搏等非药物治疗,但膈肌起搏在婴幼儿中应用较少;常见呼吸支持方法有气管切开正压通气、无创双水平正压通气和负压通气。本例患儿确诊后,在治疗肺动脉高压的同时,在睡眠时给予无创双水平正压通气治疗,6个月后肺动脉压力降至正常(图3(B)),房室腔基本恢复正常大小(图3(C));复查胸片示心胸比正常(图3(A)),氧饱和度亦维持在正常范围,未再发生低氧血症等通气不足表现。虽然无创双水平正压通气治疗可使CCHS患儿病情明显好转,然而该病好发于新生儿期,患者多数年龄小、配合度差,且临床医生对该病的认识不足,这些因素极大影响了无创正压通气治疗的推广,导致该病病死率一直较高;因此该病一经确诊,临床医生应积极通过多种办法让患儿家属接受无创正压通气治疗理念,以改善患儿生活质量,提高生存率。

致 谢

该病例报道已获得患儿家属的知情同意,感谢患儿家属积极配合,提供给我们非常宝贵的临床资料。

文章引用:
单光颂, 王本臻, 李晶, 曲妮燕, 纪志娴, 李自普. 以肺动脉高压为首发症状的先天性中枢性低通气综合征一例[J]. 亚洲儿科病例研究, 2019, 7(1): 1-6. https://doi.org/10.12677/ACRP.2019.71001

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