Abstract
心-面-皮肤(cardio-facio-cutaneous，CFC)综合征是一种极其罕见的常染色体显性遗传病。患者的主要特征为颅面部畸形、心脏畸形、皮肤异常、语言和运动发育迟缓、胃肠道功能障碍、智力障碍及癫痫。本例患儿具有典型的CFC综合征面容以及发育迟滞。二代测序技术结果显示：患儿BRAF(NM_004333.5)基因14号外显子上存在1个突变位点c.1741A>G(p. Asn581Asp)(杂合)，其父母均未发现上述变异，该变异可能为新生突变。本病尚没有特效的治疗方法。
Keywords: 心-面-皮肤综合征, BRAF基因, 突变
Abstract
Cardio-facio-cutaneous (CFC) syndrome is an extremely rare autosomal dominant genetic disease due to BRAF and other gene mutations. The main characteristics of the patients are craniofacial deformities, cardiac malformations, skin abnormalities, delay of language and motor development, gastrointestinal dysfunction, intellectual disability, and epilepsy. In this case, the child has a typical CFC syndrome face and developmental delay. The gene results of the second-generation sequencing technology showed that there was a mutation site c.1741A>G (p. Asn581Asp) (heterozygous) in exon 14 of the BRAF (NM_004333.5) gene. The mutation was not observed in the child’s parents. The above-mentioned mutation may be a de novo mutation. There is no effective therapy for this disease so far.
Keywords: cardio-facio-cutaneous syndrome, BRAF gene, mutation
心-面-皮肤(cardio-facio-cutaneous，CFC)综合征是一种常染色体显性遗传病。1986年由Reynolds等[1]首次报道。CFC综合征属于肾素-血管紧张素系统(renin-angiotensin system，RAS)心肌病群疾病之一[2]，其最常见的临床表现是颅面部畸形、心脏畸形、皮肤异常、语言和运动发育迟缓、胃肠道功能障碍、智力障碍及癫痫等。因该疾病极其罕见，临床医生对该疾病认识及研究不足，故对其诊断、鉴别诊断以及治疗较为困难。现将2019年7月就诊于中南大学湘雅医院儿科门诊的CFC综合征患儿的临床表现和诊断思路报告如下，同时复习相关文献，以期能加深临床医生对该病的认识。
1. 病例资料
1.1. 病史
患儿，男，3岁8个月，主诉“发育落后2年余”就诊。在患儿1岁时，家长发现其能独走、跑、跳，但不稳，易摔倒，语言发育欠佳，仅可发单音，可执行简单的指令。患儿为其母亲的第1胎第1产，为足月顺产儿，出生时体重3.9 kg。其家长否认患儿有宫内窘迫及生后窒息史。患儿4个月会竖头，6个月会坐，1岁能独站，1岁7个月能独走。患儿的父母体健，非近亲婚配。家族中无传染性及遗传疾病患者。
1.2. 体格检查
患儿体重18 kg，身高98 cm，生命体征平稳，神志清，精神可，有内眦赘皮，眼距宽，鼻梁塌，小下颌，双耳位低，毛发稀疏，皮肤粗糙，无皮疹及色素沉着。心率110 min-1，胸骨左缘上方可闻及II~III级收缩期杂音，双侧呼吸音清，未闻及啰音，四肢肌力、肌张力正常，生理反射存在，病理反射未引出。
1.3. 主要实验室检查
血常规、心肌酶、离子、甲状腺功能三项及同型半胱氨酸均未见明显异常。血糖为4.86 mmol/L。血氨为13.3 μmol/L。心电图示窦性心律不齐，电轴右偏，T波倒置。心脏彩色超声波检查示肺动脉瓣狭窄(中度)。脑电图大致正常。头颅MRI未见明显异常。染色体核型为46，XY。未检测到可以明确解释患者表型的致病性或疑似致病性基因拷贝数变异(copy number variations，CNV)。基因检测发现患儿BRAF(NM_004333.5)基因14号外显子c.1741A>G(p. Asn581Asp)(杂合)新生突变。其父母均无上述变异(图1)。
图1.
患儿及父母BRAF基因突变测序
Figure 1 BRAF gene mutation analysis of child and his parents
2. 讨 论
自CFC综合征被报道以来，其临床表现逐渐清晰。CFC综合征是由于基因突变导致Ras/Raf/MAPK信号通路不断活化，进而干扰细胞的增殖、分化、运动、凋亡及衰老等正常过程的一种常染色体显性遗传性疾病[3]，为罕见的遗传性疾病[4]。该病患儿临床上均表现为特有的异常面容：相对畸形大头，额头高大，双颞侧变窄，下巴小，毛发卷曲、稀少、易断，眉毛及睫毛稀少或缺如，上睑下垂，睑裂下斜，内眦赘皮褶皱，鼻基底部过宽，球状鼻头，鼻孔前倾，嘴大，人中沟深，耳朵低垂、后翻等；可合并出现咬合不良、高唇系带、高颚弓等牙齿表型及斜视、屈光不正、眼球震颤、视神经发育不全等眼科症状[5-7]；并且还会出现肺动脉瓣狭窄或其他瓣膜发育异常、肥厚性心肌病、房间隔缺损、室间隔缺损、心律失常等不同类型的心血管疾病[6-7]，干燥症、鱼鳞病、毛发角化症、瘢痕性红斑、湿疹、血管瘤、多发色素痣、皮肤过度角化、黑棘皮病等[8]不同程度的皮肤病变，性早熟、高泌乳素血症、尿崩症等内分泌异常[9]，生长发育迟缓及智能障碍，严重程度不一的神经系统疾病[4]，甚至有可能并发急性淋巴细胞白血病、淋巴瘤等肿瘤[10]。CFC综合征与Noonan综合征、Costello综合征一起被归类为RAS心肌病群[2, 11-12]。Niihori等[13]于2006年报道2例由BRAF c.1741A>G(p. Asn581Asp)导致的CFC综合征患者，表现为高额头、双颞变窄、眼眶脊发育不全等特殊面部特征，同时有心脏缺陷，毛发稀少，皮肤角化过度的症状。Hazan等[14]于2012年报道1例CFC综合征患者，其亦由BRAF c.1741A>G(p. Asn581Asp)突变导致，该例患者除有上述CFC综合征典型临床表现外，还表现有跟腱紧张。而本例患儿主要表现为运动和语言发育均迟缓、特征性面容、皮肤干燥、肺动脉瓣狭窄等，这些临床表现均为CFC综合征的典型表现。
CFC综合征的诊断需要依赖于临床表现、实验室检查以及二代测序技术等基因检测手段[15]。部分患儿在实验室血液相关检测中可发现血常规、心肌酶、肾功能、胰岛素、胰岛素样生长因子、生长激素等存在异常。但仅根据患儿的临床表现及实验室血液相关检查，很难确诊。该病的确诊仅能依靠基因检测[16-17]并结合临床表现、实验室检查。本例患儿实验室血液相关检测并未见明显异常。
CFC综合征主要由BRAF、MAP2K1、MAP2K2及KRAS 4种基因突变导致[6, 18]。其中BRAF基因突变约占CFC综合征患儿的75%，MAP2K1与MAP2K2基因突变约占25%，KRAS基因突变占2%~3%[19-20]。BRAF基因位于人类染色体7q34上，约为190 kb，包含18个外显子，编码651个氨基酸，分子量为72.5 kD(1 D=1 u)[21]。BRAF基因包含RAF蛋白激酶的所有3个保守区域，即假定的锌指区域、富含丝氨酸/苏氨酸区域及C末端激酶结构域。BRAF基因编码RAF家族丝氨酸/苏氨酸蛋白激酶。该蛋白在调节RAS/MAPK/ERK信号通路中起重要作用，影响细胞分裂、分化和分泌，调控炎症、凋亡、癌化、肿瘤细胞的侵袭和转移等多种生理活动。BRAF基因突变引起RAS/MAPK通路中编码酪氨酸激酶受体(receptor tyrosine kinases，TRK)、RAS蛋白、RAS功能的调节器以及下游信号传感器激活失败，进而导致包括CFC综合征亚型在内的7种RAS通路病[5, 22]。此外，BRAF还可以导致黑色素瘤、大肠癌、非霍奇金淋巴瘤、甲状腺癌、非小细胞肺癌、多毛细胞白血病和腺肺癌等人体各种癌症的发生，其中以黑色素瘤最为常见[23]。
笔者以“BRAF”为检索词，检索中国知网(CNKI)、万方(建库至2019年10月)、PubMed(建库至2019年10月)、HGMD及在线人类孟德尔遗传(OMIM)数据库，发现迄今已报道410种BRAF基因突变，中国仅有4篇[15, 20, 24-25]文章报道了5例基因突变导致的CFC综合征，其中BRAF基因突变2例，MAP2K1基因突变2例，KRAS基因突变1例。笔者将国内外文献报道的410种BRAF基因突变中与CFC综合征有关的基因突变共102例的资料进行总结，发现有67种致病突变(表1)，其中错义突变65种，缺失2种；16种突变良性变异(表2)；12种突变的临床意义未明(表3)，7种的致病性有争议(表4)。本例CFC综合征患儿的基因检测结果为BRAF(NM_004333.5)14号外显子c.1741A>G(p. Asn581Asp)(杂合)基因新生突变。
表1.
BRAF基因突变位点(致病突变)
Table 1 BRAF gene mutation site (pathogenic mutation)
| 序号 | Variation location | 序号 | Variation location |
|---|---|---|---|
| 1 | g.140778060T>G | 35 | c.1497A>C (p. Lys499Asn) |
| 2 | g.140781600T>G | 36 | c.1495A>G (p. Lys499Glu) |
| 3 | g.140781598_140781603del | 37 | c.1493T>A (p. Phe498Tyr) |
| 4 | c.2135C>A (p. Ala712Asp) | 38 | c.1460T>G (p. Val487Gly) |
| 5 | c.1914T>G (p. Asp638Glu) | 39 | c.1455G>T (p. Leu485Phe) |
| 6 | c.1914T>A (p. Asp638Glu) | 40 | c.1455G>C (p. Leu485Phe) |
| 7 | c.1802A>C (p. Lys601Thr) | 41 | c.1454T>C (p. Leu485Ser) |
| 8 | c.1802A>T (p. Lys601Ile) | 42 | c.1449A>C (p. Lys483Asn) |
| 9 | c.1801A>C (p. Lys601Gln) | 43 | c.1447A>C (p. Lys483Gln) |
| 10 | c.1799T>A (p. Val600Glu) | 44 | c.1442C>A (p. Ala481Glu) |
| 11 | c.1796C>G (p. Thr599Arg) | 45 | c.1411G>A (p. Val471Ile) |
| 12 | c.1796C>T (p. Thr599Ile) | 46 | c.1408_1410del (p. Thr470del) |
| 13 | c.1789C>G (p. Leu597Val) | 47 | c.1409C>G (p. Thr470Arg) |
| 14 | c.1787G>T (p. Gly596Val) | 48 | c.1406G>A (p. Gly469Glu) |
| 15 | c.1785T>A (p. Phe595Leu) | 49 | c.1405G>C (p. Gly469Arg) |
| 16 | c.1785T>G (p. Phe595Leu) | 50 | c.1403T>C (p. Phe468Ser) |
| 17 | c.1783T>C (p. Phe595Leu) | 51 | c.1399T>G (p. Ser467Ala) |
| 18 | c.1782T>G (p. Asp594Glu) | 52 | c.1391G>C (p. Gly464Ala) |
| 19 | c.1743T>A (p. Asn581Lys) | 53 | c.1391G>T (p. Gly464Val) |
| 20 | c.1741A>G (p. Asn581Asp) | 54 | c.1390G>A (p. Gly464Arg) |
| 21 | c.1726G>T (p. Asp576Tyr) | 55 | c.1390G>C (p. Gly464Arg) |
| 22 | c.1722C>G (p. His574Gln) | 56 | c.785A>G (p. Gln262Arg) |
| 23 | c.1720C>T (p. His574Tyr) | 57 | c.785A>C (p. Gln262Pro) |
| 24 | c.1695T>G (p. Asp565Glu) | 58 | c.784C>A (p. Gln262Lys) |
| 25 | c.1600G>C (p. Gly534Arg) | 59 | c.770A>G (p. Gln257Arg) |
| 26 | c.1595G>A (p. Cys532Tyr) | 60 | c.769C>A (p. Gln257Lys) |
| 27 | c.1593G>T (p. Trp531Cys) | 61 | c.739T>G (p. Phe247Val) |
| 28 | c.1592G>T (p. Trp531Leu) | 62 | c.736G>C (p. Ala246Pro) |
| 29 | c.1502A>T (p. Glu501Val) | 63 | c.735A>T (p. Leu245Phe) |
| 30 | c.1502A>C (p. Glu501Ala) | 64 | c.735A>C (p. Leu245Phe) |
| 31 | c.1502A>G (p. Glu501Gly) | 65 | c.730A>C (p. Thr244Pro) |
| 32 | c.1501G>C (p. Glu501Gln) | 66 | c.722C>T (p. Thr241Met) |
| 33 | c.1501G>A (p. Glu501Lys) | 67 | c.721A>C (p. Thr241Pro) |
| 34 | c.1497A>T (p. Lys499Asn) |
该表所有突变位点来源于人类孟德尔遗传(OMIM)数据库及PudMed数据库(建库至2019年10月)。
表2.
BRAF基因突变位点(良性变异)
Table 2 BRAF gene mutation site (benign)
| 序号 | Variation location |
|---|---|
| 1 | c.*387G>A |
| 2 | c.*111C>T |
| 3 | c.2235A>G (p. Leu745=) |
| 4 | c.2128-5del |
| 5 | c.1929A>G (p. Gly643=) |
| 6 | c.1694+14G>A |
| 7 | c.1383A>G (p. Gln461=) |
| 8 | c.1332G>A (p. Arg444=) |
| 9 | c.1227A>G (p. Ser409=) |
| 10 | c.1068A>G (p. Gln356=) |
| 11 | c.708C>T (p. Asn236=) |
| 12 | c.375T>G (p. Ser125=) |
| 13 | c.78G>T (p. Glu26Asp) |
| 14 | c.36G>A (p. Ala12=) |
| 15 | c.-5A>G |
| 16 | c.-19C>T |
表3.
BRAF基因突变位点(临床意义未明)
Table 3 BRAF gene mutation site (uncertain clinical significance)
| 序号 | Variation location |
|---|---|
| 1 | c.*3C>T |
| 2 | c.2128-4del |
| 3 | c.2128-16_2128-15del |
| 4 | c.2128-27_2128-16delinsTCT |
| 5 | c.2128-36dup |
| 6 | c.1940A>G (p. Tyr647Cys) |
| 7 | c.1799T>G (p. Val600Gly) |
| 8 | c.1781A>T (p. Asp594Val) |
| 9 | c.1382A>G (p. Gln461Arg) |
| 10 | c.1237G>A (p. Val413Met) |
| 11 | c.1166G>A (p. Arg389His) |
| 12 | c.437G>A (p. Arg146Gln) |
表4.
BRAF基因突变位点(存在争议)
Table 4 BRAF gene mutation site (conflicting interpretations of pathogenicity)
| 序号 | Variation location |
|---|---|
| 1 | c.*7T>C |
| 2 | c.2128-15dup |
| 3 | c.1411G>T (p. Val471Phe) |
| 4 | c.1391G>A (p. Gly464Glu) |
| 5 | c.1024A>G (p. Ile342Val) |
| 6 | c.981-14C>A |
| 7 | c.722C>A (p. Thr241Lys) |
CFC综合征具有基因-表型相关性。BRAF基因突变导致约50%的CFC综合征患者出现肺动脉瓣狭窄、肥厚型心肌病、房间隔缺损等心血管病变[26]，可伴有中-重度智力障碍以及喂养困难等。BRAF基因c.770A>G(p.Gln257Arg)患者具有共同的表型特征，包括特征性的相貌、心脏缺陷、身材矮小、发育不良、头颅影像学检查异常、骨骼肌肉及眼部异常及相对轻微的生长发育迟缓[13, 18]。Siegel等[27]研究报道携带MAP2K1或MAP2K2基因致病变异的个体比携带BRAF基因致病变异的个体更容易发生毛囊角化症和形成进展性痣。江转南等[22]报道MAP2K1或MAP2K2基因突变可能与早产、室间隔缺损、泌尿生殖系统或皮肤组织异常有关。本例BRAF基因 c.1741A>G(p.Asn581Asp)突变患儿表现为特征性面容、肺动脉瓣狭窄、轻微的生长发育迟缓等。
对于CFC综合征尚没有特效的治疗方案，只能根据患者的临床症状进行多学科的对症治疗，并进行定期随诊。Inoue等[28]通过建立新的BRAF 基因敲除小鼠模型及应用ERK通路抑制剂进行产前治疗为CFC综合征患者的治疗带来了希望。本例患儿已经通过肺动脉瓣切开术解决了肺动脉瓣狭窄的问题，目前仍在做语言及运动的康复训练。
总之，由于CFC综合征为多系统病变，临床医生应该加强对此类极其罕见的遗传性疾病的了解及认识，以尽早发现诊断线索，同时开展多学科团队(multiple disciplinary team，MDT)协作，为CFC综合征患儿提供相应治疗，使其临床症状得到缓解。但该疾病预后不良，应加强婚育的优生指导，同时在临床上应积极开展产前咨询和基因检测，以利于产前诊断。
基金资助
国家重点研发计划(2016YFC1306202)；国家自然科学基金(81771408)；湖南省重点领域研发计划(2019SK2081)。
This work was supported by the National Key R&D Program (2016YFC1306202), and the National Natural Science Foundation (81771408), and the Hunan Key Research and Development Program (2019SK2081), China.
利益冲突声明
作者声称无任何利益冲突。
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202104432.pdf
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