Aelvoet Y, Verloo P, Vanlander A, Vande Velde S, Van Biervliet S, De Bruyne P, Hoste L, Dheedene A, Pottie L, Hoorens A, Mendes M, De Bruyne R
Department of Pediatrics Princess Elisabeth Children's Hospital Ghent Belgium.
Faculty of Medicine and Health Science Ghent University Ghent Belgium.
JIMD Rep. 2025 Apr 4;66(3):e70013. doi: 10.1002/jmd2.70013. eCollection 2025 May.
Biallelic variants in or are associated with reduced cytoplasmic phenylalanyl-tRNA synthetase (FARS1) activity and underlie a multisystem syndrome characterized by growth limitation, developmental delay, brain calcifications, interstitial lung disease (ILD), and liver involvement. ILD is an early characteristic feature marked by bilateral ground-glass opacification, subpleural cysts, and cholesterol pneumonitis and seems to be the leading cause of disease burden and death. A 7-year-old Iraqi girl was referred with idiopathic liver disease. Her previous medical history revealed neonatal jaundice, failure to thrive (FTT), mild motor development delay, and variceal bleeding at the age of 6 years in Iraq. She was diagnosed with liver cirrhosis, severe splenomegaly, profound thrombocytopenia, and hypoalbuminemia. Her younger brother presented to our hospital at the age of 2 months with neonatal cholestasis progressing to hepatic failure with impaired synthetic function. He suffered from coagulopathy, intractable hypoalbuminemia, FTT with axial hypotonia, multiple infectious episodes, and a prothrombotic state. Whole exome sequencing revealed compound heterozygous missense variants p.(Pro226Leu) and p.(Arg475Trp) in (OMIM: 602918) in both siblings. Even in the absence of overt clinical symptoms, chest computer tomography following diagnosis showed ILD in both siblings. Decreased FARS1 activity was measured in fibroblasts of both patients. We are the first to report on two siblings with neonatal jaundice evolving to severe liver disease as a cardinal symptom of cytosolic FARS deficiency. We emphasize the importance of performing a pulmonary workup in the diagnostic process of liver failure of unknown origin for detection of ILD as a clue to diagnosis.
或中的双等位基因变异与细胞质苯丙氨酰 - tRNA合成酶（FARS1）活性降低有关，并构成一种多系统综合征的基础，该综合征的特征为生长受限、发育迟缓、脑钙化、间质性肺病（ILD）和肝脏受累。ILD是一种早期特征性表现，以双侧磨玻璃样混浊、胸膜下囊肿和胆固醇性肺炎为标志，似乎是疾病负担和死亡的主要原因。一名7岁的伊拉克女孩因特发性肝病前来就诊。她既往病史显示有新生儿黄疸、生长发育不良（FTT）、轻度运动发育迟缓，以及在伊拉克6岁时出现静脉曲张出血。她被诊断为肝硬化、严重脾肿大、严重血小板减少和低白蛋白血症。她的弟弟在2个月大时因新生儿胆汁淤积进展为肝功能衰竭并伴有合成功能受损而到我院就诊。他患有凝血病、顽固性低白蛋白血症、伴有轴性肌张力低下的FTT、多次感染发作以及血栓前状态。全外显子组测序显示，两名患儿均存在（OMIM：602918）基因的复合杂合错义变异p.(Pro226Leu)和p.(Arg475Trp)。即使在没有明显临床症状的情况下，诊断后胸部计算机断层扫描显示两名患儿均有ILD。在两名患者的成纤维细胞中检测到FARS1活性降低。我们首次报道了两名新生儿黄疸演变为严重肝病的患儿，这是胞质FARS缺乏的主要症状。我们强调在不明原因肝功能衰竭的诊断过程中进行肺部检查以检测ILD作为诊断线索的重要性。
