应该怀疑 遗传嵌合体 当患者出现：
- 不对称生长障碍。
- 伴有斑片状分布的皮肤色素病变（例如牛奶咖啡斑、痣等），特别是沿着布拉什科线分布的情况。
- 合并血管畸形。
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1.
Biesecker LG，Spinner NB。镶嵌现象和人类疾病的基因组观点。 Nat Rev Genet [互联网]。 2013 年 5 月[引用于 2015 年 10 月 2 日]；14(5):307–20。可从： http://www.nature.com/nrg/journal/v14/n5/abs/nrg3424.html
皮肤镶嵌和镶嵌神经皮肤疾病。
- 色素性皮肤嵌合体的存在是神经发育障碍的危险因素（高达 56% 存在皮外表现，可能是神经、骨骼、内分泌等方面的表现）。
- 花叶病可能有多种潜在的遗传原因，从点突变到染色体重排。
- 不同类型的花叶病的鉴别诊断很困难。它们的特点是表现出非常广泛的表型谱和高度的临床变异性，因为嵌合现象的本质是具有不同遗传密码的多个细胞群的组合，并且它们的分布和比例是随机的。
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1.
Kromann AB、Ousager LB、Ali IKM、Aydemir N、Bygum A。色素镶嵌：原始文献综述和未来处理建议。 Orphanet 罕见疾病杂志 [互联网]。 2018 年 3 月 5 日[引用于 2019 年 7 月 20 日]；13(1):39。可从： https://doi.org/10.1186/s13023-018-0778-6
镶嵌染色体重排（CNV）。
- 有一些综合征具有独特的马赛克表现，例如 帕利斯特-基利安综合征.
单基因花叶病。
- 这些是常染色体显性遗传的疾病。
- 其中一些在其构成表现上与生命不相容（它们导致流产或胎儿死亡，例如儿童综合症），因为受影响的基因具有高度的进化重要性，因此只有具有减弱表型的嵌合体才能存活。
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1.
Ruggieri M、Praticò PD、Happle R。马赛克神经皮肤疾病及其原因。小儿神经病学研讨会[互联网]。 2015 年 11 月 13 日 [引自 2015 年 11 月 13 日]；可从： http://www.sciencedirect.com/science/article/pii/S1071909115000765
脑镶嵌和脑畸形：
- 有些大脑畸形是由于嵌合突变而发生的。
- 畸形的解剖分布可以帮助推断它是一种嵌合病，因此神经影像学对于规划遗传研究很有用。
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1.
罗丹 RE，沃尔什 CA。小儿神经系统疾病中的体细胞突变。小儿神经病学[互联网]。 2018 年 [引自 2018 年 12 月 4 日]；87:20–2。可从： https://linkinghub.elsevier.com/retrieve/pii/S0887899418308580
脑嵌合体的诊断技术。
遗传嵌合现象在外周血中通常无法检测到，因此有必要在受影响的组织中进行研究。
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1.
Ye Z、McQuillan L、Poduri A、Green TE、Matsumoto N、Mefford HC 等。体细胞突变：大脑畸形和局灶性癫痫的隐藏遗传学。癫痫研究[互联网]。 2019 年 [引自 2019 年 8 月 20 日]；155:106161。可从： https://linkinghub.elsevier.com/retrieve/pii/S0920121119301810
嵌合体的遗传和遗传咨询。
- 花叶病是由于个体本身发生的从头合子后突变而发生的，并且不是遗传的（根据定义）。
- 只有当受影响的个体是种系突变（种系嵌合体）的携带者时，它们才会被传播。
- 如果疾病被传播，后代的临床表现将不会是马赛克，而是以体质突变的形式出现。
具体治疗
- 对于一些嵌合体疾病，特别是那些影响 PI3K/AKT 通路和 RAS/RAF 通路基因的疾病，有特定的治疗替代方案。
诊断协议
🧠🧬 临床算法：色素性皮肤镶嵌→神经发育风险
1️⃣确认皮肤图案真的是blaschkoid
临床要点:
- 躯干呈“S”形，背部呈“V”形，四肢呈曲线形
- 尊重中线（非皮肤科、非血管）
- 节段性色素沉着过度或不足
👉 是的 不 Blaschko 继续→相关遗传嵌合的可能性较低。
2️⃣ 神经系统风险的初步分层
🔴 高风险（≥1 个标准）：
- 广泛或双侧病变
- 面部或头皮受累
- 关联于：
- 发育迟缓
- 癫痫
- 张力减退/痉挛
- 宏观/小头畸形
- 畸形特征
- 身体不对称
➡️直接进行扩展的神经学和遗传学研究。
🟡 中度风险：
- 受伤有限
- 无症状儿童或有轻度发育疑虑的儿童
- 神经系统检查正常
➡️结构化随访+神经心理学筛查。
🟢低风险：
- 小的局部病变
- 没有其他发现
- 明显正常发育
➡️临床随访，无需初始侵入性测试。
3️⃣ 推荐的神经系统评估
🔹永远
- 详细的发展历史
- 有针对性的神经系统检查
- 语言筛选和执行功能
🔹如果有临床怀疑
- 脑电图:
- 危机、倒退、TDL 波动
- 脑部 MRI（如果可能，3T）:
- 癫痫
- 总体延迟
- 神经不对称
- 疑似皮质畸形
📌 即使大脑嵌合，MRI 也可以正常→正常≠排除。
4️⃣ 遗传学研究：订购什么以及在什么组织中进行
❌ 什么还不够
- 阵列或外显子组 只存在于血液中 （经常出现假阴性）
✔️推荐策略（交错）
1级
- 血液中的阵列 CGH 或 SNP 阵列
- 检测非整倍体或高百分比 CNV
- 如果存在畸形或整体延迟，则很有用
2 级（如果怀疑仍然存在）
- 受影响皮肤的基因研究
- 穿刺活检
- 理想情况下：
- 靶向NGS
- 高深度临床外显子组
- 受影响的皮肤与血液的比较
3级（特定表型）
- 根据诊所指示的小组：
- 癫痫（PI3K-AKT-mTOR、MTOR、PIK3CA）
- 色素/神经皮肤疾病
- 自闭症谱系障碍 + 大头畸形
📌 马赛克 <10% 要求深度>300×.
5️⃣ 具有更大神经相关性的皮肤图案
| 皮肤图案 | 神经系统风险 |
|---|---|
| 广泛性伊藤色素减退症 | 🔴高 |
| 双边布拉什科 | 🔴高 |
| 身体不对称造成的伤害 | 🔴高 |
| 本地化分段 | 🟡变量 |
| 小孤立点 | 🟢低 |
6️⃣ 神经发育监测
即使无症状：
- 每 6-12 个月进行一次发育评估
- 语言、注意力、协调性
- 早期干预门槛低
👉许多表型 进化的，不完全是先天性的。
7️⃣ 给家人的关键信息（非常重要）
- ❌并不暗示与IVF有过错或因果关系
- ✔️这是一个早期的生物学发现
- ✔️ 大多数儿童 不会发展成严重残疾
- ✔️及早发现 改善功能预后
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https://neuropediatoolkit.org/wp-content/plugins/zotpress/
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1.
金斯勒弗吉尼亚州。影响色素沉着的马赛克疾病 - 第 2 部分：如何进行基因诊断。 Br J Dermatol [互联网]。 2025 年 12 月 1 日[引用于 2025 年 12 月 20 日]；193(6):1047–55。可从： https://doi.org/10.1093/bjd/ljaf224