一家系2例先天性红细胞生成性卟啉病并文献复习

Two siblings with congenital erythropoietic porphyria in one family: case report and literature review

摘要

例1，女，7岁；例2，男（例1胞弟），3岁。2例患儿均在出生后出现粉红色尿，光照部位（颜面部、双手）出现皮肤水疱，继而破溃、结痂、瘢痕形成，关节挛缩导致活动障碍等临床表现。2例患儿基因检测均为UROS基因c.776T>C（p.Leu259Pro）纯合变异，确诊为UROS基因变异常染色体隐性遗传性先天性红细胞生成性卟啉病。该病例报道提示，对于不明原因婴幼儿期溶血性贫血、粉红色尿、严重光敏性皮炎者，应考虑先天性红细胞生成性卟啉病可能，尽早完善基因检测，提早干预治疗改善预后。

Abstract

Case 1 was a 7-year-old girl; Case 2 was her 3-year-old younger brother. Both children developed pink urine shortly after birth and exhibited blistering on photo-exposed areas (face and hands), followed by ulceration, crusting, scarring, and joint contractures leading to impaired mobility. Genetic testing in both patients identified a homozygous variant in the UROS gene, c.776T>C (p.Leu259Pro), confirming autosomal recessive congenital erythropoietic porphyria due to UROS mutations. This case report highlights that congenital erythropoietic porphyria should be considered in infants and young children with unexplained hemolytic anemia, pink urine, and severe photosensitive dermatitis. Early genetic testing is recommended to facilitate timely intervention and improve outcomes.

Graphical abstract

关键词

先天性红细胞生成性卟啉病 / 皮肤 / 光敏性损害 / 儿童

Key words

Congenital erythropoietic porphyria / Skin / Photosensitivity / Child

1 病例资料

例1，女，7岁，因双手、双足、面部皮肤反复水疱6年余入院。患儿在新生儿期因病理性黄疸行光疗时出现皮肤大疱，破溃。此后颜面部、双手、双足皮肤反复水疱、破溃、局部皮肤增厚或结痂后形成瘢痕。患儿一直在外院就诊，予以局部用药，病情反复。体格检查：暴露的皮肤可见色素沉着或色素减停；颜面部皮肤发黑、多毛，双手皮肤局部增厚，瘢痕形成致部分手指挛缩，浅表淋巴结未触及，牙齿黑黄，心脏、肺部、腹部触诊及听诊无异常。血常规示WBC计数4.9×10⁹/L［参考值：（4.3~11.3）×10⁹/L］，WBC分类正常，血红蛋白107 g/L（参考值：118~156 g/L），血小板220×10⁹/L［参考值：（167~453）×10⁹/L］。尿常规：尿液褐色，潜血阴性，胆红素（2+），尿胆原（4+）。肝肾功能、心肌酶、血糖均正常。腹部彩超提示脾大。Woods灯照射下尿液呈粉红色荧光。见图1。基因检测：编码尿卟啉原Ⅲ合成酶（uroporphyrinogen Ⅲ synthase, UROS）的基因纯合突变，c.776T>C（p.Le u259Pro）。见图2。确诊为先天性红细胞生成性卟啉病（congenital erythropoietic porphyria, CEP）。

例2是例1的胞弟，男，3岁。因皮肤反复水疱2年余入院。体查：皮肤发黑，毛发旺盛，散在水疱疹，有抓痕，部分可见结痂。心脏、肺部、腹部触诊及听诊无异常。血常规示WBC计数7.5×10⁹/L，血红蛋白110 g/L，血小板计数117×10⁹/L，平均红细胞体积72.6 fl（参考值：76.0~78.0 fl）；尿常规：尿色淡黄色，潜血阴性，白细胞酯酶（2+），尿胆原（+），亚硝酸盐（+）；肝肾功能、心肌酶基本正常。腹部彩超提示脾大。Woods灯下尿液呈粉红色荧光。基因检测：UROS基因纯合突变，c.776T>C（p.Leu259Pro）。见图2。综合上述资料，患儿确诊为CEP。

2 讨论

CEP于1911年由Gunther首先描述，又称为Gunther病^［1］，是一种罕见的常染色体隐性遗传性疾病，发病率<0.9/100万^［2］。CEP是第一个被描述与卟啉代谢紊乱有关的人类卟啉症，是UROS活性降低（或缺乏）或GATA1基因突变引起的血红素生物合成缺陷所致^［3］。UROS可催化线性四吡咯羟甲基胆素转化为环化四吡咯尿卟啉原Ⅲ，CEP患儿由于UROS缺陷，这一过程受阻，最终生成无法代谢为血红素的非生理性卟啉。卟啉化合物具有高度的光敏性，会吸收波长为400~410 nm的紫外线，从而产生能量，发生荧光和化学反应，导致细胞膜的完整性和功能丧失，细胞器破坏和细胞死亡。骨髓和红细胞卟啉化合物积累，红细胞被破坏，造成溶血性贫血。卟啉随血液扩散，皮肤暴露在阳光下可出现水疱，水疱破裂后不易愈合，易反复感染，产生溃疡，久之则形成瘢痕。手指关节处皮肤产生瘢痕后会造成指关节挛缩，手指活动障碍。脾脏从血液中摄取更多被破坏的红细胞导致不同程度的脾大，血小板计数，WBC计数相应减少^［1，4］。卟啉通过尿液和粪便排出，在胎儿期羊水呈红色或生后出现粉红色尿。卟啉与磷酸钙结合力增加，代谢物沉积在牙釉质中出现红色牙，易患牙周炎，在骨结构会造成鼻软骨和耳软骨破坏，手指关节出现骨质溶解等。患者眼睛暴露在阳光条件下，易产生角膜溃疡、眼睑下垂、坏死性巩膜炎、脂溢性睑缘炎、角膜结膜炎和硬化性角膜炎等^［3-6］。

CEP临床表现多样，影响疾病严重程度的主要因素是UROS的残余活性水平以及由此造成的过量Ⅰ型卟啉积累^［7］。早期识别和早期干预至关重要。严重病例可在宫内出现症状，常常为宫内死胎或死产。大部分患儿在新生儿期或婴儿期出现症状，本文报道的2例均在新生儿期出现症状。所有患儿均有光敏性皮肤损害，其他常见临床表现依次为：红色尿、血液系统受累、骨骼改变及眼部改变。部分患儿在新生儿期出现呼吸窘迫综合征、低血容量休克或肝功能障碍等表现。尽管症状出现早，由于医师对本病认识不足，诊断年龄明显延误，文献报道病例多数至学龄期得以诊断，有9例患儿在14岁以后才得以诊断，最晚诊断的是一位日本女性患者，在88岁才明确诊断^［6-12］。本文报道的2例患儿，均未能早期诊断。文献中也有多个家庭聚集病例，明显加重了家庭和社会经济负担。因此，对有不明原因的宫内死胎，羊水颜色异常或出生后典型的皮肤光敏性损害，均需要警惕CEP，早期行尿Woods灯检测、尿卟啉水平和UROS活性检测，有条件单位，应行基因检测。

人类基因库（http://www.hgmd.org）关于CEP目前报道的基因突变有60余种，其中大多数为错义突变，且主要见于白种人群，c.217T>C是白种人中最常见的突变，其次是c.10C>T和c.683C>T；在亚洲国家，基因突变报道的数据很少，突变谱似乎与西方人群不同^［13］。国内关于CEP的病例报道20余例，其中仅2例进行了基因诊断，1例为c.416T>C，另一例具体突变不详，我们报道的2例基因改变c.776T>C也是人类基因库中没有登记的。一些基因型和临床表型相关性也有报道。由于c.217T>C突变蛋白具有热力学不稳定性，常与更严重的疾病表现和不良预后相关，尤其错义突变。文献报道的8例宫内出现症状的患儿其基因型均为c.217T>C^［14-16］；30例在新生儿和婴儿期出现症状的患儿中有8例系c.217T>C纯合或杂合突变^{［6，8，13，16-26］}。GATA1基因突变常常与贫血、血小板减少、胎儿血红蛋白升高有关^{［13，27］}。

CEP的治疗有限，早期诊断和避光生活至关重要。防止皮肤、眼睛损害，减轻因皮肤瘢痕继发的关节挛缩和关节活动障碍，并需日常补充维生素D。对于慢性溶血性贫血患者，可输注浓缩红细胞以降低体内红细胞的生成，从而降低卟啉的积累，但需注意长期输血可能导致铁过载。此外，可口服活性炭，结合从胆汁排出的卟啉，促进血液和皮肤中卟啉从胆汁和粪便中排出。有脾功能亢进的患儿可行脾切除治疗，也有研究认为这些措施并不能让病人获益或改善其健康相关的生活质量，避光生活仍是最重要的措施^［28］。有患者从放血治疗中获益，地拉罗司治疗引起的缺铁可改善骨髓中的红细胞分化，减轻溶血和光敏性^{［16，22］}。有研究表明异常蛋白质稳态是导致UROS缺乏的普遍机制，动物实验中证实蛋白酶体抑制剂硼替佐米可以减少外周血红细胞和尿中的卟啉沉积，逆转皮肤光敏性，可作为一种治疗选择^［29-30］。也有用羟基脲减少骨髓卟啉的合成来治疗CEP的报道^［31］。对于严重病例，异基因造血干细胞移植（hematopoietic stem cell transplantation, HSCT）是目前唯一有效的治疗方案，HSCT后卟啉代谢接近正常，皮肤症状和血液学改变可以完全纠正，骨骼、眼部病变不再进展。迄今为止，在文献中已经报道了大约20例，最晚移植年龄为46岁，其中移植后最长存活时间目前记录的为20余年^{［13-14，16，20，24，26，32］}。作为一种遗传代谢性疾病，CEP的HSCT治疗仍面临诸多挑战，其中最重要的是原发移植失败和移植后致死性肝功能衰竭，因此目前HSCT主要用于以下情况：（1）新生儿期严重表现；（2）慢性溶血伴输血依赖性贫血；（3）与已知的严重形式相关的特殊基因型（如纯合子C73R）^{［11，13，16，26，33-36］}。随着移植手段的不断进步和移植前更加完善的评估和干预，HSCT的适应证可能会进一步拓宽。目前已经在动物实验中证实了CEP基因治疗的有效性^［37-38］，随着基因工程技术的不断进步，基因治疗可能成为未来CEP治疗方法之一。

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