甲基丙二酸尿症相关肺高血压临床特点与基因突变

发布时间：2018-08-14 18:22

【摘要】：目的:总结15例以肺高血压(pulmonary hypertension,PH)为突出表现的甲基丙二酸尿症(methylmalonic aciduria,MMA)患儿临床特点及基因检测结果,提高对甲基丙二酸尿症相关PH临床表现的认识及诊治水平。方法:回顾性分析2012年5月至2016年5月北京大学第一医院儿科诊断治疗的15例以PH为突出表现的MMA患儿临床特点、诊断治疗经过、基因突变分析及随访结果,MMA的诊断标准为尿中甲基丙二酸水平正常值的100倍,检测血浆总同型半胱氨酸(homocysteine,Hcy)和脑利钠肽(brain natriuretic peptide,BNP)水平。PH的诊断标准采用多普勒超声经三尖瓣反流估测的肺动脉收缩压(pulmonary arterial systolic pressure,PASP)40 mm Hg(1 mm Hg=0.133 k Pa)。结果:(1)起病特点:15例患儿中男10例,女5例,年龄0.5~13.8岁,平均(5.0±4.3)岁,PH起病年龄(3.7±3.5)岁,其中早发型5例,晚发型10例,10例PH症状为MMA首发表现,5例在MMA起病后3~72个月出现PH症状。(2)临床表现:气促和/或呼吸困难11例,口唇发绀11例,乏力和/或活动耐力下降6例,水肿4例;PH国际卫生组织功能分级(WHO FC)为Ⅱ级4例,Ⅲ级5例,Ⅵ级6例,平均(3.1±0.8)级。(3)多系统损害:肾损害14例,表现为血尿及蛋白尿,5例为慢性肾脏病(chronic kidney disease,CKD),8例大细胞性贫血,4例伴轻-中度智力运动发育落后,5例亚临床甲状腺功能减低。(4)辅助检查:15例患儿经超声心动图三尖瓣反流测量的肺动脉收缩压49~135 mm Hg,平均(90.3±23.9)mm Hg;血浆总Hcy显著升高[35.0~221.0μmol/L,平均(121.2±48.2)μmol/L],其中11例100μmol/L;12例血BNP水平不同程度升高[21.0~4995.0 ng/L,中位值794 ng/L,其中12例300 ng/L],血气分析发现存在不同程度低氧血症,动脉血氧饱和度平均81.4%±8.4%(70%~94%)。(5)肺部高分辨CT(high resolusion CT,HRCT):9例小叶中心磨玻璃密度结节及肺小叶间隔增厚,提示肺静脉闭塞病(pulmonary veno-occlusive disease,POVD),其中3例伴肺部炎症或肺水肿,另3例伴弥漫间质浸润呈网格样改变,提示肺间质病变。(6)基因检测结果:10例均为MMACHC基因复合杂合突变(cbl C型),共发现5种已报道突变,其中10例c.80AG突变,6例同时存在c.609GA突变。(7)治疗及随访结果:所有患儿均给予羟钴胺肌肉注射及甜菜碱等治疗,11例给予肺动脉高压靶向药物,住院治疗后PASP、血Hcy、BNP均显著降低,2例死亡,13例随访11~64个月,平均(27.5±19.0)个月,临床症状均缓解,除1例外,肺动脉压力均在3~6个月恢复至正常,随访PH无复发,多系统损害明显恢复。结论:PH是MMA合并型的严重并发症,多发生于晚发型男性患儿,临床以气促、呼吸困难和发绀症状为突出表现,多存在低氧血症,HRCT多呈POVD改变,PH常与肾受累同时存在,及时诊断并给予针对MMA的治疗以及恰当抗PH治疗,肺动脉压力短期内多可恢复正常,重症患儿可危及生命。MMACHC基因c.80AG可能是MMA相关PH的热点突变。
[Abstract]:Objective: to summarize the clinical characteristics and gene detection results of 15 children with pulmonary hypertensionPH (methylmalonic aciduriaMMA), and to improve the understanding and diagnosis and treatment of PH associated with methylmalonuria. Methods: from May 2012 to May 2016, 15 children with MMA, who were diagnosed and treated by pediatrics in the first Hospital of Peking University, were retrospectively analyzed. The results of gene mutation analysis and follow-up showed that the diagnostic criteria of MMA were 100 times of the normal level of methylmalonic acid in urine. Detection of plasma total homocysteine and brain natriuretic peptide (brain natriuretic peptidea. The diagnostic criteria for the diagnosis of pulmonary artery systolic pressure by Doppler echocardiography (pulmonary arterial systolic pressure PASP 40 mm Hg (1 mm Hg=0.133 k Pa). By tricuspid regurgitation Results: (1) among the 15 cases, 10 cases were males and 5 cases were females. The mean age of PH was (5.0 卤4.3) years old, and the age of onset was (3.7 卤3.5) years old. Among them, 5 cases had early onset, and the mean age was (5.0 卤4.3) years old and the onset age was (3.7 卤3.5) years old. The first manifestation of MMA was PH in 10 patients with late onset of PH (n = 5). (2) the clinical manifestations were dyspnea and / or dyspnea in 11 cases, cyanosis in lips in 11 cases, fatigue and / or decreased activity endurance in 6 cases. There were 4 cases of edema with (WHO FC) grade 鈪，

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