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Novel Methionyl-Trna Synthetase Gene Variants/ Phenotypes in Interstitial Lung and Liver Disease: a Case Report and Review of Literature

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Novel Methionyl-Trna Synthetase Gene Variants/ Phenotypes in Interstitial Lung and Liver Disease: a Case Report and Review of Literature Submit a Manuscript: http://www.f6publishing.com World J Gastroenterol 2018 September 28; 24(36): 4208-4216 DOI: 10.3748/wjg.v24.i36.4208 ISSN 1007-9327 (print) ISSN 2219-2840 (online) CASE REPORT Novel methionyl-tRNA synthetase gene variants/ phenotypes in interstitial lung and liver disease: A case report and review of literature Kuerbanjiang Abuduxikuer, Jia-Yan Feng, Yi Lu, Xin-Bao Xie, Lian Chen, Jian-She Wang Kuerbanjiang Abuduxikuer, Yi Lu, Xin-Bao Xie, Jian-She licenses/by-nc/4.0/ Wang, Department of Hepatology, Children’s Hospital of Fudan University, Shanghai 201102, China Manuscript source: Unsolicited manuscript Jia-Yan Feng, Lian Chen, Department of Pathology, Children’s Correspondence to: Jian-She Wang, MD, PhD, Professor, Hospital of Fudan University, Shanghai 201102, China Department of Hepatology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, Jian-She Wang, Department of Pediatrics, Jinshan Hospital of China. [email protected] Fudan University, Shanghai 201508, China Telephone: +86-21-64931171 Fax: +86-21-64931171 ORCID number: Kuerbanjiang Abuduxikuer (0000-0003 -0298-3269); Jia-Yan Feng (0000-0002-6651-4675); Yi Lu Received: June 21, 2018 (0000-0002-3311-4501); Xin-Bao Xie (0000-0002-3692 Peer-review started: June 22, 2018 -7356); Lian Chen (0000-0002-0545-2108); Jian-She Wang First decision: July 31, 2018 (0000-0003-0823-586X). Revised: August 2, 2018 Accepted: August 24, 2018 Author contributions: Wang JS designed the report and Article in press: August 24, 2018 approved the final submission; Abuduxikuer K collected data, Published online: September 28, 2018 analyzed relevant information, and wrote the manuscript; Wang JS, Lu Y, Xie XB, and Abuduxikuer K clinically managed the patient; Feng JY, Chen L analyzed liver biopsy samples. Supported by the National Natural Science Foundation of Abstract China, No. 81570468. Interstitial lung and liver disease (ILLD) is caused by biallelic mutations in the methionyl-tRNA synthetase Informed consent statement: Informed consent was obtained (MARS) gene. To date, no genetic changes other than from the parents. missense variants were reported in the literature. Here, Conflict-of-interest statement: The authors declare that they we report a five-month old female infant with typical have no conflicts of interest. ILLD (failure to thrive, developmental delay, jaundice, diffuse interstitial lung disease, hepatomegaly with CARE Checklist (2013) statement: The authors have read the severe steatosis, anemia, and thrombocytosis) showing CARE Checklist (2013), and the manuscript was prepared and novel phenotypes such as kidney stones, acetabular revised according to the CARE Checklist (2013). dysplasia, prolonged fever, and extreme leukocytosis. Whole exome sequencing revealed a novel truncating Open-Access: This article is an open-access article which was variant (c.2158C>T/p.Gln720Stop) together with a selected by an in-house editor and fully peer-reviewed by external novel tri-nucleotide insertion (c.893_894insTCG that reviewers. It is distributed in accordance with the Creative caused the insertion of an arginine at amino acid Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this position 299) in the MARS gene. work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and Key words: Methionyl-tRNA synthetase; Infant; Kidney the use is non-commercial. See: http://creativecommons.org/ stone; Hip dysplasia; Leukocytosis; Interstitial lung and WJG|www.wjgnet.com 4208 September 28, 2018|Volume 24|Issue 36| Abuduxikuer K et al . Novel MARS variants and phenotypes in ILLD liver disease; Methionyl-trna synthetase gene failure to thrive, developmental delay, jaundice, and dark urine. She was born full-term with a normal birth © The Author(s) 2018. Published by Baishideng Publishing weight (3100 g) after an uncomplicated first pregnancy Group Inc. All rights reserved. and vaginal delivery. Weight gain and developmental milestones were normal until three months of age Core tip: Previously reported cases of interstitial lung (weighted 6000 g), when she failed to thrive with a and liver disease (ILLD) were associated with biallelic body weight of 5700 g at the age of 5 mo without the missense mutations in the methionyl-tRNA synthetase ability of rolling over. (MARS ) gene. Here, we report a Chinese infant with At in-patient admission, this patient was 5.2 mo typical ILLD (failure to thrive, developmental delay, old with a body weight of 5500 g (2nd percentile by interstitial lung disease, cholestasis, hepatomegaly, WHO standards), length of 55 cm (lower than the steatosis, anemia, and thrombocytosis) with novel st 1 percentile), and head circumference of 39 cm phenotypes, such as kidney stones, acetabular (2nd percentile). This infant had prolonged low-grade dysplasia, prolonged fever, and extreme leukocytosis. fever, pulmonary effusion, diffuse interstitial lung Whole exome sequencing revealed a novel truncating disease, significant leukocytosis, high procalcitonin variant (c.2158C>T/p.Gln720Stop), and a novel tri- nucleotide insertion (c.893_894insTCG) in the MARS (PCT)/CRP levels, and required nasal oxygen therapy. gene. Despite the resolution of cholestasis, this patient Serial chest X-rays showed some improvement in died of respiratory failure at the age of 11 mo. pulmonary effusion, but no improvement in interstitial lung involvement (Figure 1A). After serial antibiotic treatments (ceftriaxone, cefoperazone + slubactam, Abuduxikuer K, Feng JY, Lu Y, Xie XB, Chen L, Wang JS. meropenem, norvancomycin, and fluconazole), body Novel methionyl-tRNA synthetase gene variants/phenotypes temperature was normalized, oxygen therapy was no in interstitial lung and liver disease: A case report and review longer needed, and leukocytosis improved, however of literature. World J Gastroenterol 2018; 24(36): 4208-4216 the interstitial lung disease stayed the same. After Available from: URL: http://www.wjgnet.com/1007-9327/full/ treatment with ursodeoxycholic acid and fat-soluble v24/i36/4208.htm DOI: http://dx.doi.org/10.3748/wjg.v24. vitamins, cholestasis improved significantly (Table 1). i36.4208 The patient was discharged with normal oxygen saturation on room air without apparent respiratory distress or cough. A liver function test and complete blood count were normal at a 9.5 mo follow-up. INTRODUCTION However, the infant was admitted to a provincial level The methionyl-tRNA synthetase (MARS) gene encodes pediatric intensive care unit for acute respiratory cytoplasmic methionyl-tRNA synthetase (MetRS) distress at 11 mo of age and received mechanical responsible for catalyzing the ligation of methionine to ventilation. Despite treatment, she died of respiratory tRNA[1]. MetRS belongs to a family of aminoacyl-tRNA failure and hypoxic encephalopathy. synthetases that play critical roles in protein biosynthesis A genetic cause was suspected due to multiple by charging tRNAs with their cognate amino acids[2]. system involvement, although a liver panel consisting Interstitial lung and liver disease (ILLD) (OMIM#615486) of 41 genes (Table 2) related to liver diseases came is caused by homozygous or compound heterozygous back negative. Lysosomal storage disease was mutations in the MARS gene (156560) on chromosome considered, but an enzyme panel for the screening of 12q13[3-5]. Heterozygous MARS mutations have been common lysosomal storage diseases was normal, as reported to be associated with autosomal dominant was the urine acidoglycoprotein level. This patient was Charcot-Marie-Tooth disease (CMT)[6-9]. The same MARS enrolled for the undiagnosed disease patient program mutation may cause both ILLD and CMT[10]. MARS is in our hospital, and whole exome sequencing was also a candidate gene for hereditary spastic paraplegias ordered. Compound heterozygous MARS gene variants, (HSPs), a neuro-degenerative motor neuron disorder[11]. c.2158C>T/p.Gln720Stop and c.893_894insTCG/ To date, no genetic changes other than missense p.Arg299dup, were detected. Presence of these variants have been reported in the literature. Here, mutations was confirmed with Sanger sequencing, we report a Chinese infant with lethal ILLD showing and parental origins were ascertained. Both variants novel phenotypes such as kidney stones, acetabular were not reported in the dbSNP137 (http://www. ncbi. dysplasia, prolonged fever, and extreme leukocytosis. nlm.nih.gov/snp/), 1000 Genome Database (http:// Whole exome sequencing revealed a novel truncating www.1000genomes.org/), and Exome Variant Server variant together with a novel tri-nucleotide insertion in (http://evs.gs.washington.edu/EVS/). The c.2158C>T the MARS gene. mutation was inherited from the healthy mother, which caused the change of a glutamine amino acid at position 720 to a stop codon, which was predicted to be disease- CASE REPORT causing by MutationTaster (http://www.mutationtaster. A five-month old female infant was presented with a org). The tri-nucleotide insertion (c.893_894insTCG) WJG|www.wjgnet.com 4209 September 28, 2018|Volume 24|Issue 36| Abuduxikuer K et al . Novel MARS variants and phenotypes in ILLD Table 1 Changes in complete blood count, procalcitonin, serum biochemistry, and blood coagulation profiles Age (mo) (1in-patient admission; 2discharge to out-patient follow-up) 5.1 5.61 6 6.2 6.5 6.8 7 7.22 9.5 Complete blood White blood cell (4-10 × 109/L) 16.9 21.1 71.7 26.4 33.7 45.8 30.3
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