Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants
Abstract Background Growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) is a rare disease caused by compound heterozygous variations in the isoleucyl-tRNA synthetase 1 (IARS1) gene. To date, only a few cases have been reported and there has been no comprehensiv...
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BMC
2025-07-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-025-03885-z |
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| author | Shu-Yuan Li Yu-Ting Wang Teng Liu |
| author_facet | Shu-Yuan Li Yu-Ting Wang Teng Liu |
| author_sort | Shu-Yuan Li |
| collection | DOAJ |
| description | Abstract Background Growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) is a rare disease caused by compound heterozygous variations in the isoleucyl-tRNA synthetase 1 (IARS1) gene. To date, only a few cases have been reported and there has been no comprehensive analysis of its clinical, pathological, molecular genetic features, or factors associated with a poor prognosis. Methods Three new cases of IARS1 deficiency have been documented. A review and summary of the clinical, pathological, and molecular genetic features of previously reported cases was conducted. The prognostic significance of identified risk factors was evaluated using Kaplan-Meier plotter analysis. Results The 3 new cases harbored 6 novel variants in IARS1. The principal clinical manifestations of IARS1 deficiency were intrauterine growth retardation (13/13), failure to thrive (13/14), feeding difficulties (10/14), elevated aminotransferases (11/14), cholestasis (8/14), acute liver failure (7/14), hepatomegaly (7/14), hypoalbuminemia (10/14), coagulation abnormalities (8/14), microcephaly (11/14), neurodevelopmental delay (10/14), hypotonia (9/14), impaired intellectual development (6/7), recurrent infections (9/14), special facial appearance (8/14), zinc deficiency (4/7), and pulmonary alveolar proteinosis (3/14). The principal pathological features of the liver were fibrosis (6/8), hepatocellular steatosis (5/8), and cholestasis (5/8). A total of 24 variants were identified in 14 cases, comprising a frameshift variant (n = 3), nonsense variant (n = 3), splice variant (n = 2), and missense variant (n = 16). Of the 14 cases, five resulted in death. Kaplan-Meier analysis indicated that the occurrence of pulmonary alveolar proteinosis (HR = 10.837, 95% CI = 1.246–94.257, P = 0.031) and anemia (HR = 15.411, 95%CI = 2.101-113.057, P = 0.007) were associated with a poor prognosis. Conclusions In this report, we present three new cases of IARS1 deficiency and provide a comprehensive summary of the clinical, pathological, and molecular genetic characteristics observed in all previously reported cases. Furthermore, our findings suggest that the presence of pulmonary alveolar proteinosis and anemia may be associated with a poor prognosis. |
| format | Article |
| id | doaj-art-4b60ece6c9ee4680abd47b82de1f4762 |
| institution | DOAJ |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-4b60ece6c9ee4680abd47b82de1f47622025-08-20T03:06:05ZengBMCOrphanet Journal of Rare Diseases1750-11722025-07-0120111610.1186/s13023-025-03885-zPulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variantsShu-Yuan Li0Yu-Ting Wang1Teng Liu2The Department of Gastroenterology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children’s Hospital of Chongqing Medical UniversityThe Department of Gastroenterology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children’s Hospital of Chongqing Medical UniversityThe Center for Pediatric Liver Diseases, Children’s Hospital of Fudan UniversityAbstract Background Growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH) is a rare disease caused by compound heterozygous variations in the isoleucyl-tRNA synthetase 1 (IARS1) gene. To date, only a few cases have been reported and there has been no comprehensive analysis of its clinical, pathological, molecular genetic features, or factors associated with a poor prognosis. Methods Three new cases of IARS1 deficiency have been documented. A review and summary of the clinical, pathological, and molecular genetic features of previously reported cases was conducted. The prognostic significance of identified risk factors was evaluated using Kaplan-Meier plotter analysis. Results The 3 new cases harbored 6 novel variants in IARS1. The principal clinical manifestations of IARS1 deficiency were intrauterine growth retardation (13/13), failure to thrive (13/14), feeding difficulties (10/14), elevated aminotransferases (11/14), cholestasis (8/14), acute liver failure (7/14), hepatomegaly (7/14), hypoalbuminemia (10/14), coagulation abnormalities (8/14), microcephaly (11/14), neurodevelopmental delay (10/14), hypotonia (9/14), impaired intellectual development (6/7), recurrent infections (9/14), special facial appearance (8/14), zinc deficiency (4/7), and pulmonary alveolar proteinosis (3/14). The principal pathological features of the liver were fibrosis (6/8), hepatocellular steatosis (5/8), and cholestasis (5/8). A total of 24 variants were identified in 14 cases, comprising a frameshift variant (n = 3), nonsense variant (n = 3), splice variant (n = 2), and missense variant (n = 16). Of the 14 cases, five resulted in death. Kaplan-Meier analysis indicated that the occurrence of pulmonary alveolar proteinosis (HR = 10.837, 95% CI = 1.246–94.257, P = 0.031) and anemia (HR = 15.411, 95%CI = 2.101-113.057, P = 0.007) were associated with a poor prognosis. Conclusions In this report, we present three new cases of IARS1 deficiency and provide a comprehensive summary of the clinical, pathological, and molecular genetic characteristics observed in all previously reported cases. Furthermore, our findings suggest that the presence of pulmonary alveolar proteinosis and anemia may be associated with a poor prognosis.https://doi.org/10.1186/s13023-025-03885-zAnemiaHepatopathyIsoleucyl-tRNA synthase 1PrognosisPulmonary alveolar proteinosis |
| spellingShingle | Shu-Yuan Li Yu-Ting Wang Teng Liu Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants Orphanet Journal of Rare Diseases Anemia Hepatopathy Isoleucyl-tRNA synthase 1 Prognosis Pulmonary alveolar proteinosis |
| title | Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants |
| title_full | Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants |
| title_fullStr | Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants |
| title_full_unstemmed | Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants |
| title_short | Pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with IARS1 variants |
| title_sort | pulmonary alveolar proteinosis and anemia may be associated with poor prognosis in patients with iars1 variants |
| topic | Anemia Hepatopathy Isoleucyl-tRNA synthase 1 Prognosis Pulmonary alveolar proteinosis |
| url | https://doi.org/10.1186/s13023-025-03885-z |
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