Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures.
Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures.
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DOI：
10.1186/s13023-022-02597-y
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发表时间：
2022-12-22
影响因子：
3.7
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中科院分区：
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进行性家族性肝内胆汁淤积症3型（PFIC 3）是由ABCB 4基因的致病性变体引起的常染色体隐性遗传病。本研究旨在探讨PFIC 3患者的ABCB 4基因型和临床表型特征。收集并分析了13例新发PFIC 3儿童患者以及PubMed和CNKI数据库中报告的82例PFIC 3儿童患者的临床和分子遗传学数据。13例新发PFIC 3患者包括6例女性和7例男性，主要表现为肝肿大、脾肿大、黄疸和瘙痒，以及γ-谷氨酰转肽酶（GGT）水平升高。检测到14种新的ABCB 4变异，其中8种被诊断为可能致病，6种为致病。在所有95例PFIC 3患者中，观察到85.3%（81/95）的肝肿大、67.4%（64/95）的瘙痒、52.6%（50/95）的脾肿大、48.4%（46/95）的黄疸、34.7%（33/95）的门脉高压症和100%（88/88）的GGT升高。66.1%（39/59）的患者对口服熊去氧胆酸（UDCA）治疗有不同程度的阳性反应，其中38.5%（15/39）的患者实验室检查完全恢复。53例（58.9%，53/90）病情稳定，37例（41.1%，37/90）临床效果不佳，其中死亡7例，27例已行肝移植，3例等待肝移植。在95名患者中共检测到96种ABCB 4变异。具有双等位基因无效变体的PFIC 3患者表现出较早的发病年龄[10.5（2，18）vs. 19（8，60）个月，p = 0.007]，较低的UDCA缓解率[18.2%（2/11）vs. 77.1%（37/48），p = 0.001]，与非双等位基因无效变体相比，临床结局更不乐观[80%（12/15）vs. 33.3%（25/75），p = 0.001]。PFIC 3表现为肝肿大、瘙痒、脾肿大和黄疸，血清GGT水平升高作为生化标志。尽管观察到UDCA治疗反应的不同程度改善，但41.1%的PFIC 3患者显示预后不良。双等位基因无效变异体的ABCB 4基因型与更高的PFIC 3表型相关。此外，本研究中的14种新变体扩展了ABCB 4突变谱，并为PFIC 3患者的诊断提供了新的分子生物标志物。在线版本包含补充材料，可通过10.1186/s13023-022-02597-y获得。
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disease caused by pathogenic variants of the gene ABCB4. This study aimed to investigate the ABCB4 genotypic and the clinical phenotypic features of PFIC3 patients. The clinical and molecular genetic data of 13 new pediatric patients with PFIC3 as well as 82 reported ones in the PubMed and CNKI databases were collected and analyzed. The 13 new PFIC3 patients included six females and seven males, and the main presentations were hepatomegaly, splenomegaly, jaundice, and pruritus, as well as increased levels of gamma-glutamyl transpeptidase (GGT). Fourteen new ABCB4 variants were detected, including eight diagnosed to be likely-pathogenic and six, pathogenic. Among all the 95 PFIC3 cases, hepatomegaly was observed in 85.3% (81/95), pruritus in 67.4% (64/95), splenomegaly in 52.6% (50/95), jaundice in 48.4% (46/95), portal hypertension in 34.7% (33/95) and GGT elevation in 100% (88/88) of the patients. Positive responses at varied degrees to oral ursodeoxycholic acid (UDCA) treatment were observed in 66.1% (39/59) of the patients, among whom 38.5% (15/39) fully recovered in terms of the laboratory changes. Although the condition remained stable in 53 patients (58.9%, 53/90), the clinical outcomes were not promising in the rest 37 cases (41.1%, 37/90), including 7 died, 27 having undergone while another 3 waiting for liver transplantation. A total of 96 ABCB4 variants were detected in the 95 patients. PFIC3 patients with biallelic null variants exhibited earlier onset ages [10.5 (2, 18) vs. 19 (8, 60) months, p = 0.007], lower UDCA response rate [18.2% (2/11) vs. 77.1% (37/48), p = 0.001], and more unpromising clinical outcomes [80% (12/15) vs. 33.3% (25/75), p = 0.001], compared with those with non-biallelic null variants. PFIC3 presented with hepatomegaly, pruritus, splenomegaly and jaundice with increased serum GGT level as a biochemistry hallmark. Although varying degrees of improvement in response to UDCA therapy were observed, 41.1% of PFIC3 patients exhibited unfavorable prognosis. ABCB4 genotypes of biallelic null variants were associated with severer PFIC3 phenotypes. Moreover, the 14 novel variants in this study expanded the ABCB4 mutation spectrum, and provided novel molecular biomarkers for diagnosis of PFIC3 patients. The online version contains supplementary material available at 10.1186/s13023-022-02597-y.
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DOI：
10.1097/mpg.0b013e31824ef36f
发表时间：
2012-08-01
影响因子：
2.9
作者：
Fang, Ling-Juan;Wang, Xiao-Hong;Wang, Jian-She
通讯作者：
Wang, Jian-She
影响因子：
3.8
作者：
Lipinski, Patryk;Ciara, Elzbieta;Jankowska, Irena
通讯作者：
Jankowska, Irena
DOI：
10.1016/s2210-7401(12)70018-9
发表时间：
2012-09-01
影响因子：
2.7
作者：
Jacquemin, Emmanuel
通讯作者：
Jacquemin, Emmanuel
影响因子：
29.4
作者：
Jacquemin, E;de Vree, JML;Elferink, RPJO
通讯作者：
Elferink, RPJO
影响因子：
3.5
作者：
Dzagania, Tamar;Engelmann, Guido;Kubitz, Ralf
通讯作者：
Kubitz, Ralf