Ponikowska Malgorzata, Pollak Agnieszka, Kotwica-Strzalek Ewa, Brodowska-Kania Dorota, Mosakowska Magdalena, Ploski Rafal, Niemczyk Stanislaw
Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, 128 Szaserów St, 04-141, Warsaw, Poland.
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63 St., 80-308, Gdansk, Poland.
BMC Med Genet. 2020 Oct 2;21(1):195. doi: 10.1186/s12881-020-01134-7.
Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome.
A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G > A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45.
Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.
阿拉吉耶综合征是一种常染色体显性疾病，通常由JAG1基因的致病变异引起。过去，胆汁淤积是诊断该综合征的必要条件。然而，基因检测的最新进展表明，临床表现从无症状到多器官受累各不相同。法洛四联症是阿拉吉耶综合征中最常见的复杂先天性心脏缺陷，极少导致需要透析的肾衰竭——文献中仅有此类病例的个别报道，且均非阿拉吉耶综合征。
一名41岁患有发绀、呼吸困难和多血质的女性入院。该患者患有慢性肾病和法洛四联症，过去曾接受布莱洛克 - 陶西格分流术姑息治疗；入院时，左分流仅保留了极少的血流量。这些症状，连同精神状态受损和面部畸形特征，促使进行了包括全外显子组测序在内的广泛临床和基因检测。在JAG1基因内鉴定出一个先前未知的错义变异c.587G＞A。由于没有胆汁淤积的迹象，且仅碱性磷酸酶水平升高提示亚临床肝脏受累，该患者被诊断为不完全性阿拉吉耶综合征。终末期肾病需要进行肾脏替代治疗。选择了持续非卧床腹膜透析，患者的生活质量显著提高。然而，在拒绝进一步治疗后，患者于45岁时死亡。
法洛四联症应始终促使临床医生评估是否患有阿拉吉耶综合征，并为患者提供早期肾脏科护理。尽管法洛四联症极少导致需要透析的终末期肾病，但如果进行姑息治疗并伴有肾脏发育异常（阿拉吉耶综合征的典型表现），则可能如本病例一样导致严重肾衰竭。此类病例尚无标准治疗方法，但根据我们的经验，腹膜透析值得考虑。最后阿拉吉耶综合征的临床诊断标准需要修订。以前，诊断基于胆汁淤积——然而，发现心血管异常更为普遍。此外，标准未包括同样常见的肾功能损害。
