發(fā)布時間：2018-08-14 18:22

【摘要】：目的:總結(jié)15例以肺高血壓(pulmonary hypertension,PH)為突出表現(xiàn)的甲基丙二酸尿癥(methylmalonic aciduria,MMA)患兒臨床特點及基因檢測結(jié)果,提高對甲基丙二酸尿癥相關(guān)PH臨床表現(xiàn)的認(rèn)識及診治水平。方法:回顧性分析2012年5月至2016年5月北京大學(xué)第一醫(yī)院兒科診斷治療的15例以PH為突出表現(xiàn)的MMA患兒臨床特點、診斷治療經(jīng)過、基因突變分析及隨訪結(jié)果,MMA的診斷標(biāo)準(zhǔn)為尿中甲基丙二酸水平正常值的100倍,檢測血漿總同型半胱氨酸(homocysteine,Hcy)和腦利鈉肽(brain natriuretic peptide,BNP)水平。PH的診斷標(biāo)準(zhǔn)采用多普勒超聲經(jīng)三尖瓣反流估測的肺動脈收縮壓(pulmonary arterial systolic pressure,PASP)40 mm Hg(1 mm Hg=0.133 k Pa)。結(jié)果:(1)起病特點:15例患兒中男10例,女5例,年齡0.5~13.8歲,平均(5.0±4.3)歲,PH起病年齡(3.7±3.5)歲,其中早發(fā)型5例,晚發(fā)型10例,10例PH癥狀為MMA首發(fā)表現(xiàn),5例在MMA起病后3~72個月出現(xiàn)PH癥狀。(2)臨床表現(xiàn):氣促和/或呼吸困難11例,口唇發(fā)紺11例,乏力和/或活動耐力下降6例,水腫4例;PH國際衛(wèi)生組織功能分級(WHO FC)為Ⅱ級4例,Ⅲ級5例,Ⅵ級6例,平均(3.1±0.8)級。(3)多系統(tǒng)損害:腎損害14例,表現(xiàn)為血尿及蛋白尿,5例為慢性腎臟病(chronic kidney disease,CKD),8例大細(xì)胞性貧血,4例伴輕-中度智力運動發(fā)育落后,5例亞臨床甲狀腺功能減低。(4)輔助檢查:15例患兒經(jīng)超聲心動圖三尖瓣反流測量的肺動脈收縮壓49~135 mm Hg,平均(90.3±23.9)mm Hg;血漿總Hcy顯著升高[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],血氣分析發(fā)現(xiàn)存在不同程度低氧血癥,動脈血氧飽和度平均81.4%±8.4%(70%~94%)。(5)肺部高分辨CT(high resolusion CT,HRCT):9例小葉中心磨玻璃密度結(jié)節(jié)及肺小葉間隔增厚,提示肺靜脈閉塞病(pulmonary veno-occlusive disease,POVD),其中3例伴肺部炎癥或肺水腫,另3例伴彌漫間質(zhì)浸潤呈網(wǎng)格樣改變,提示肺間質(zhì)病變。(6)基因檢測結(jié)果:10例均為MMACHC基因復(fù)合雜合突變(cbl C型),共發(fā)現(xiàn)5種已報道突變,其中10例c.80AG突變,6例同時存在c.609GA突變。(7)治療及隨訪結(jié)果:所有患兒均給予羥鈷胺肌肉注射及甜菜堿等治療,11例給予肺動脈高壓靶向藥物,住院治療后PASP、血Hcy、BNP均顯著降低,2例死亡,13例隨訪11~64個月,平均(27.5±19.0)個月,臨床癥狀均緩解,除1例外,肺動脈壓力均在3~6個月恢復(fù)至正常,隨訪PH無復(fù)發(fā),多系統(tǒng)損害明顯恢復(fù)。結(jié)論:PH是MMA合并型的嚴(yán)重并發(fā)癥,多發(fā)生于晚發(fā)型男性患兒,臨床以氣促、呼吸困難和發(fā)紺癥狀為突出表現(xiàn),多存在低氧血癥,HRCT多呈POVD改變,PH常與腎受累同時存在,及時診斷并給予針對MMA的治療以及恰當(dāng)抗PH治療,肺動脈壓力短期內(nèi)多可恢復(fù)正常,重癥患兒可危及生命。MMACHC基因c.80AG可能是MMA相關(guān)PH的熱點突變。
[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 鹵4.3) years old, and the age of onset was (3.7 鹵3.5) years old. Among them, 5 cases had early onset, and the mean age was (5.0 鹵4.3) years old and the onset age was (3.7 鹵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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