Neonatal Ichthyosis and Sclerosing Cholangitis Syndrome: Extremely Variable Liver Disease Severity From Claudin-1 Deficiency
Neonatal Ichthyosis and Sclerosing Cholangitis Syndrome: Extremely Variable Liver Disease Severity From Claudin-1 Deficiency
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新生儿鱼鳞病和硬化性胆管炎综合征：Claudin-1 缺乏导致的肝病严重程度差异极大
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发表时间：
2011
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通讯作者：
E. Sokal
中科院分区：
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作者：
M. Paganelli;X. Stephenne;A. Gilis;E. Jacquemin;A. Caude;M. Girard;E. Gonzales;N. Revencu;R. Reding;C. Wanty;F. Smets;E. Sokal
肝细胞和胆管细胞之间的紧密连接在将胆汁流与血浆分离的过程中发挥着重要作用。许多胆汁淤积性疾病中都充分描述了紧密连接的继发性改变，这些疾病会导致细胞旁通透性增加和随后的肝损伤 (1)。紧密连接的核心蛋白由紧密连接蛋白和闭合蛋白链组成。 Claudin-1 是 Claudin 家族的成员，在肝脏和皮肤中表达，定位于染色体 3q27-q28。 CLDN1 基因纯合突变被证明会导致一种罕见的常染色体隐性综合征，将新生儿鱼鳞病与硬化性胆管炎相关（NISCH 综合征），并首次在 2 个不相关的摩洛哥家庭中被描述 (2,3)。到目前为止，只有来自 4 个不同家庭的 8 名患者被描述为受到这种综合征的影响 (2-5)。他们患有鱼鳞病和新生儿胆汁淤积性黄疸。胆汁淤积从短暂缓解形式到更严重的纤维化情况 (2-5)。两名患者需要肝移植（3,5）。其中之一显示移植后皮肤损伤和脱发有所消退 (3)。我们在这里描述了 4 名来自摩洛哥近交家庭的新患者，所有患者都表现出 NISCH 综合征的临床特征和 CLDN1 基因突变。 (6,7)。这里描述的患者和之前报道的患者胆红素 2.8mg/dL），血清 ALT 和 GGT 正常。静脉注射维生素 K 后，INR 恢复正常，出血得到缓解。肝脏超声检查未见异常。使用 99mTc-IDA 进行的肝胆闪烁扫描显示，放射性核素肝脏摄取略有减少，并且没有排泄。进行了肝活检，结果显示小叶间胆管正常、门管间隙正常、小叶结构规则，伴有细胞内和小管胆汁淤积。皮肤活检显示正角化、角化过度和颗粒层增生。头发显微镜检查发现脱发和结节性脱发的局灶性区域。血细胞涂片未见胞质内空泡。基因检测显示与她姐姐相同的纯合 CLDN1 基因突变，证实了 NISCH 综合征的诊断。该患者接受了 20 毫克/公斤/天的熊去氧胆酸 (UDCA) 和 ADEK 维生素补充剂治疗。生化胆汁淤积和身体体征得到解决，在 4 年随访中，她仅抱怨轻度瘙痒和皮肤干燥，并通过保湿局部疗法治疗。
T ight junctions between hepatocytes and cholangiocytes play a fundamental role in separating bile flow from plasma. Secondary alterations of tight junctions are well described in many cholestatic disorders inducing an increase in paracellular per-meability and subsequent liver damage (1). The core proteins of tight junctions are composed of strands of claudins and occludin. Claudin-1 is a member of the claudin family expressed in liver and skin and mapping on chromosome 3q27-q28. The CLDN1 gene homozygous mutation was shown to cause a rare autosomal reces- sive syndrome associating neonatal ichthyosis to sclerosing cholangitis (NISCH syndrome) and first described in 2 unrelated Moroccan families (2,3). Only 8 patients, from 4 different families, have been described as affected by this syndrome so far (2–5). They presented with ichthyosis and neonatal cholestatic jaundice. Cholestasis varied from a transient remitting form to more severe fibrogenic conditions (2–5). Two patients required liver transplantation (3,5). One of them showed regression of skin lesions and alopecia after the transplant (3). We describe here 4 new patients from an inbred family of Moroccan origins, all presenting with the clinical features of NISCH syndrome and a mutation of the CLDN1 gene. (6,7). patients described here and of previously reported patients bilirubin 2.8mg/dL), with normal serum ALT and GGT. After vitamin K intravenous injection, INR normalized and bleeding resolved. Liver ultrasonography was unremarkable. A hepatobiliary scintigraphy with 99mTc-IDA revealed a mild reduction of radio-nuclide liver uptake and absence of its excretion. A liver biopsy was performed and showed normal interlobular bile ducts, normal portal spaces, and regular lobular architecture with intracellular and canalicular cholestasis. Skin biopsy showed orthokeratosis, hyper-keratosis, and granular layer hyperplasia. Microscopic examination of the hair revealed trichoptilosis and focal area of trichorrhexis nodosa. No intracytoplasmic vacuoles were seen in blood cell smears. Genetic testing revealed the same homozygous CLDN1 gene mutation as in her elder sister, confirming the diagnosis of NISCH syndrome. The patient was treated with 20mg/kg/day of ursodeoxycholic acid (UDCA) and ADEK vitamin supplement- ation. Biochemical cholestasis and physical signs resolved and at 4-year follow-up she complained only of mild pruritus and dry skin, which were treated by moisturizing topical therapy.