| 一般情况 | |
|---|---|
| 品种：短毛猫 |
| 年龄：9岁 | |
| 性别：雄 | |
| 是否绝育：是 | |
| 诊断：少汗性外胚层发育不良 | |
01 主诉及病史
因四肢和腹部瘙痒就诊。7岁时被一家救助机构收养。一直定期接受外部抗寄生虫治疗。有慢性鼻炎病史。
02 检查
四肢和腹部出现了弥漫性脱毛，大腿内侧脱毛和色素沉着，脚趾脱毛也很明显（下图）。被毛检查发现，底毛减少或消失，只有护毛存在。还出现了弥漫性鳞状上皮细胞增多、毛囊铸型、弥漫性红斑和皮肤弹性的整体丧失。毛发脱落的情况自猫被收养以来就一直存在，而红斑和瘙痒则是在发病前几周出现的。
↑ 弥漫性毛发稀少。(a)腹部完全脱毛，剩余的毛皮上没有底毛。(b)大腿内侧出现脱毛和色素沉着。(c)脚趾脱毛。
口腔检查发现，只有六颗牙齿，四颗犬齿和两颗下前臼齿。门牙、上前臼齿和臼齿均已缺失。犬齿和前臼齿呈不正常的圆锥形（下图）。
↑ 牙齿异常。只有四颗犬齿和两颗下前臼齿，且形状异常、极尖。门齿、上前臼齿和臼齿缺失。(a)四颗犬齿清晰可见。(b)右下前臼齿用箭头表示。
血液学和生化检查显示中度嗜酸性粒细胞增多和中性粒细胞白细胞增多，可能是继发于慢性皮肤病。腹部超声检查显示肾上腺正常，呈正常回声，大小和形状正常，血液和尿液检查正常，尿比重正常，为1.050，排除了库欣综合征。
FIV和FelV检测结果均为阴性。主人拒绝对其进行进一步的组织病理学检查。
由于出现了毛发稀少、鳞状上皮细胞增多、毛囊铸型和牙齿缺失等临床症状，同时排除了库欣综合征等代谢性疾病，因此怀疑是少汗性外胚层发育不良（HED）。
03 基因检测
对该猫的基因组进行了测序，并将测序数据与96个不同基因的对照基因组进行了比较，以寻找可能的致病变异。分析确定了X染色体上的一个变体 NC_058386.1:g.57,148,944G>A。这是EDA基因中的一个错义变异，XM_011291781.3:c.1042G>A，预测在蛋白质水平上将丙氨酸变为苏氨酸残基，XP_011290083.1:p. (Ala348Thr)。这个预测的氨基酸替换位于EDA的C-端信号转导结构域（下图）。
04 讨论
1875年，查尔斯-达尔文对印度一个四代同堂的印度教家庭进行了研究，该家庭中有10名男性亲属患有少汗性外胚层发育不良（hypohidrotic ectodermal dysplasia，HED），达尔文对该病进行了最早的科学描述[1]。这些研究使他推断出了X连锁隐性遗传的基本原理[1]。
人类HED的临床表型包括毛发稀疏或缺失、牙齿异常，表现为部分牙齿缺失和剩余牙齿呈现独特的尖状形态，以及各种腺体（尤其是汗腺）缺乏，导致怕热[2]。这种表型也被称为克里斯-西门子-图雷纳综合征（Christ-Siemens-Touraine syndrome）[3]。
大多数人类HED患者的X染色体EDA基因编码的Ectodysplasin A（EDA）蛋白存在功能缺失变异[2,4]。EDA是一种同源三聚体II型跨膜蛋白，具有胞内N-端、单跨膜结构域、胞外短胶原样结构域和C-端信号结构域[5-7]。替代剪接产生了来自约400 kb EDA基因的两种替代转录本，它们编码两种蛋白质异构体，分别称为EDA-A1和EDA-A2，这两种异构体因C-端信号结构域中两个氨基酸的存在或缺失而不同，并与两种不同的受体结合[8]。
较短的EDA-A2异构体及其受体的生理功能尚不清楚。在胎儿发育过程中，较长的EDA-A1异构体的表达会促使许多不同的外胚层附属物（如毛囊、牙芽或汗腺）的形成。信号级联涉及呋喃蛋白酶对膜结合的EDA-A1进行细胞外蛋白水解，释放出一种旁分泌型三聚体信号分子。释放出的可溶性片段可与靶细胞上的EDA受体（EDAR）结合。活化的EDAR会招募一种称为EDARADD的细胞内适配蛋白，该复合物会激活NF-κB信号，从而调节靶基因的表达[9]。
尽管EDA、EDAR或EDARADD的功能缺失会导致人类患者出现相同的临床表型[10,11]，但绝大多数人类患者是由于EDA变异所致，这种特殊形式的病症被称为X连锁HED（XHED）。由EDAR或EDARADD变异导致的常染色体隐性或显性遗传的HED非常罕见。
在小鼠[5,6]、狗[13-16]和牛[17-28]中，也有导致HED的EDA变异报道。EDA缺乏的狗已被成功地用作治疗试验的动物模型，这些试验目前正在人类患者身上进行[29,30]。
本研究调查了一只患有综合表型的雄性猫，它的毛发部分缺失，牙齿缺失或形状异常。这种综合临床症状被归类为HED。这种表型极具特征性，尤其是在雄性个体中，X染色体EDA是主要的功能性候选基因。
对于兽医来说，重要的是要考虑到所有可能受XHED影响的器官系统，以便对未来可能出现的病例进行最佳管理。应特别注意妥善处理呼吸道感染，并监测受XHED影响的动物可能因腺体缺陷而引起的眼部不适。
总之，本研究报告了一只雄猫的临床表型，这只猫患有XHED。 与其他哺乳动物的XHED相似，该病的主要表型改变包括毛发部分缺失和底毛完全缺失。此外，患猫缺少大部分牙齿，剩余的牙齿呈不正常的锥形。遗传调查发现，EDA:c.1042G>A是最可能的致病缺陷。这是首例与EDA相关的猫HED病例。
文献来源：Rietmann SJ, Cochet-Faivre N, Dropsy H, Jagannathan V, Chevallier L, Leeb T. EDA Missense Variant in a Cat with X-Linked Hypohidrotic Ectodermal Dysplasia. Genes (Basel). 2024 Jun 28;15(7):854.
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