Peroutka Christina, Salas Jacqueline, Britton Jacquelyn, Bishop Juliet, Kratz Lisa, Gilmore Maureen M, Fahrner Jill A, Golden W Christopher, Wang Tao
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
JIMD Rep. 2019;45:71-76. doi: 10.1007/8904_2018_143. Epub 2018 Oct 23.
Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented.
We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient.
This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.
胞质亮氨酸 - 转运RNA合成酶（LARS）中的有害突变会导致1型婴儿肝衰竭综合征（ILFS1），这是一种最近才被认识到的罕见常染色体隐性疾病（OMIM151350）。文献中仅报道了6个患有ILFS1的家庭。ILFS1患者通常在5至24个月大时被诊断出来，表现为发育不良、发育迟缓、脑病、小细胞贫血以及慢性肝功能障碍，在儿童患病后会反复加重。这种疾病的新生儿表现尚未得到充分记录。
我们报告了一名早产女婴，她有子宫内生长受限、发育不良、先天性贫血、全身性水肿和暴发性肝衰竭，最终导致致命的多器官衰竭。该婴儿的肝衰竭特征是肝脏合成功能受损不成比例，包括严重的凝血病和低白蛋白血症，在疾病早期肝脏解毒功能无明显缺陷，也没有肝细胞损伤的证据。对患儿及其父母进行的全外显子测序在该患者中发现了LARS基因的两个遗传性错义突变。其中一个，c.1292T>A；p.Val431Asp，已在ILFS1患者中报道过，而另一个，c.725C>T；p.Pro242Leu，是新发现的。这两个突变都涉及LARS高度保守的编辑结构域中的氨基酸残基，预计在功能上是有害的，可能导致了该患者的临床表现。
这是第一例记录ILFS1新生儿表现的病例，突出了肝脏合成功能早期、严重且不成比例的缺陷。及时诊断ILFS1对于指导关键的临床管理和改善这种罕见且可能危及生命的疾病的治疗结果至关重要。
