Ahn, Kyung Jin
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Yoon, Ja Kyoung
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Kim, Gi Beom
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Kwon, Bo Sang
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Go, Jung Min
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Moon, Jin Su
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Bae, Eun Jung
(Department of Pediatrics, Seoul National University Children's Hospital)
,
Noh, Chung Il
(Department of Pediatrics, Seoul National University Children's Hospital)
Purpose: Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a cri...
Purpose: Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis. Methods: We conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013. Results: The first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001). Conclusion: The group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome.
Purpose: Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis. Methods: We conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013. Results: The first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001). Conclusion: The group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome.
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문제 정의
Two patients confirmed the JAG1 mutation, and the other had not performed the chromosomal study because of death before full evaluation. These findings imply that the poor outcome of the patients with tetralogy of Fallot in AGS is notable and the tetralogy of Fallot with pulmonary atresia is needed for additional study about investigation of AGS.
This study describes the clinical characteristics and the significant prognostic factors of AGS at a single center in Korea. There is a paucity of literature on the outcome with AGS and the correlation of each presentation in Korea.
제안 방법
He confirmed the JAG1 mutation. For regression of severe peripheral pulmonary stenosis, he underwent total 5 times of balloon angioplasty including cutting balloon procedures. The first procedure was done at 3 years of age.
Of the 36 patients, 12 patients underwent cardiac catheterizations, 6 underwent diagnostic procedures, 4 underwent balloon angioplasty, and 2 underwent percutaneous valvuloplasty procedures. There were a mean of 1.
Two patients died within 30 postoperative days. One of them was diagnosed with tetralogy of Fallot with pulmonary atresia combined with major aorto-pulmonary collateral arteries (MAPCAs), and underwent 2 operations, namely right ventricular outflow track reconstruction and unifocalization of MAPCAs with angioplasty of the pulmonary arteries. After the second operation, he had extracorporeal membrane oxygenation (ECMO) and died from ECMO weaning failure.
83 years of age. She had an emergency decompression operation for intracranial epidural hemorrhage on postoperative day 1, and died of multiorgan failure following brain death. Intracranial bleeding is a major cause of morbidity and mortality17,25).
We obtained the liver biopsy findings via ultrasonography-guided biopsy or wedge resection. To evaluate the existence of hepatocellular carcinoma, we investigated the radiologic readings and the serum alpha-fetoprotein in patients with suspected AGS. Severe liver disease was defined based on the necessity of invasive intervention that was indicated by one or more of the following: (1) serum total bilirubin level >15 mg/dL; (2) who had liver cirrhosis/liver tumor; (3) who underwent liver transplantation; and (4) Kasai operation.
대상 데이터
Cardiac surgery was performed in 12 patients. The patients underwent a mean of 1.
We excluded 8 cases; 7 suspected AGS patients who were lost to follow-up until diagnosis, and 1 suspected AGS patient who died before the diagnosis was confirmed. Finally, 41 patients who were diagnosed with AGS were included in the study. The inclusion criteria were as follows: (1) positive for ≥3 clinical criteria (chronic cholestasis, congenital heart disease, butterfly vertebrae, posterior embryotoxon, and peculiar face); and (2) positive for ≥1 clinical criteria with a proven JAG1 mutation3,7,10).
The patients had manifested first features as follows: jaundice (58.5%), murmur (7.3%), cyanosis (4.9%), jaundice with murmur (12.2%), jaundice with small bowel obstruction (2.4%), and cardiac anomaly detected during the prenatal period via fetal echocardiography (14.6%). The median age of onset was 1.
The study population comprised 23 boys and 18 girls. Of the 41 patients enrolled, 35 met ≥3 clinical criteria, and 6 met ≥1 clinical criteria with a proven JAG1 gene mutation.
데이터처리
Categorical data were compared using the chi-square test with Yate’s correction if indicated. Continuous data were compared using the t test. Survivorship analysis was performed according to the Kaplan-Meier method, with right-censored data for no event or missing data.
이론/모형
Continuous data were compared using the t test. Survivorship analysis was performed according to the Kaplan-Meier method, with right-censored data for no event or missing data. A P value of <0.
372). The Aristotle score was used to determine the procedure-adjusted complexity score. The 4 patients had an Aristotle score of ≥9.
The severe heart disease was defined based on the need for intervention or the critical condition having heart failure, hypoxemia, or hemodynamic instability. The complexity of the cardiac operation was determined using the Aristotle score11).
성능/효과
(A) The survival rate was worse in patients with a cardiac anomaly that was detected via fetal ultrasonography than in those with later cardiac presentation (50% at fetal ultrasonography vs. 75.0% at 1–4 months vs. 90.5% at 0–30 days vs. 100% at >5 months, P=0.009).
(B) Overall survival was worse in patients with combined severe diseases than in those with only severe liver disease or severe heart disease, or in those without severe disease (28.6% with combined severe diseases vs. 75.0% with severe liver disease vs. 100% with severe heart disease vs. 100% without severe disease, P<0.001).
Given our finding that the complexity of cardiac operation with an Aristotle score of ≥9 and a maximum total bilirubin level on postoperative day 30 of ≥15 mg/dL was a poor prognostic factor, the presence of higher bilirubin during the postoperative period could be worsen the morbidity/mortality associated with the cardiac operation.
Eight patients died at a median age of 4 years (range, 3 months to 15 years). The 5-year survival was 75% with severe liver disease, and 16.7% with combined severities of liver and heart. The causes of death are described in Table 2.
There was no significant difference in age of onset between the patients who had presenting jaundice and those who had presenting cardiac features such as fetal cardiac anomaly or cyanosis or cardiac murmur (2.03±4.43 months vs. 0.91±2.03 months, respectively, P=0.34).
Of the 41 patients enrolled, 35 met ≥3 clinical criteria, and 6 met ≥1 clinical criteria with a proven JAG1 gene mutation. With regard to the clinical criteria, 34 patients (82.9%) displayed chronic cholestasis, 36 (87.8%) displayed congenital heart disease, 37 (92.5%; except for one, which was undetermined) displayed a peculiar face, 13 (31.7%) displayed butterfly vertebrae, and 12 (30.0%; except for one, which was undetermined) posterior embryotoxon. An analysis of the JAG1 gene was performed in 28 patients, with 27 subjects showing the JAG1 gene mutation, and one subject showing several polymorphisms but no mutations.
후속연구
Our study has a limitation because our data treated total bilirubin only. Further studies are needed to investigate about the relationship between conjugated bilirubin and prognosis.
참고문헌 (25)
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