Syndromic Congenital Heart Disease Diagnosed in Adulthood: A Reminder of the Phenotypic Variability of Alagille Syndrome

Alagille syndrome: A nutritional niche for Notch

Progressive familial intrahepatic cholestasis (PFIC) and to a lesser extent, Alagille syndrome, often lead to end-stage liver disease during childhood. We report our experience of DNA-based prenatal diagnosis of PFIC1-3 and Alagille syndrome. Four molecular antenatal diagnoses were performed in 3 PFIC families and 17 in 11 Alagille syndrome families. DNA was isolated from chorionic villus or cultured amniocyte samples from women, without pregnancy complications. All four foetuses with a family history of PFIC1, 2, or 3 were heterozygous for an ATP8B1, ABCB11, or ABCB4 mutation and pregnancies were continued. Three of the infants were healthy after birth, and 1 premature infant, who had an ABCB4 mutation, experienced transient neonatal cholestasis. Among the families with a history of de novo JAG1 mutation, none of the foetuses was mutated, versus 40% of those with a history of familial mutation. Of 4 pregnant women with a JAG1-mutated foetus, 3 cut short their pregnancy and 1 gave birth to a child with overt Alagille syndrome. Molecular antenatal diagnosis of PFIC1-3 and Alagille syndrome is reliable because clinical outcome after birth corresponded to molecular foetal data.

Background: The early diagnosis of ALGS is crucial because the disease is often a variable expression, and the symptoms are similar to other pathologies, especially biliary tract atrophy. The primary objective of this study was determined of the ratio of JAG1 and NOTCH2 gene mutation characteristics in children with Alagille syndrome (ALGS). Methods: Batch description of the cases was performed on 32 pediatric patients with ALGS treated at Childrend’s Hospital 1 from February 2015 to December 2018. Results: Based on the study of 32 children with ALGS, the following results were obtained: The JAG1 gene mutation detection rate is 75%; No instances of NOTCH2 gene mutation were detected. The meaningless mutation rate was 33%, the false means was 29%, the split frame was 21%, the cutting connector was 13%, and the loss of the small segment was 4%. Mutations were distributed on most exons, and the surge screening ratio of JAG1 patient’s relatives with mutations was 23.5%. Conclusion: Results indicated that early diagnosis of ALGS based on JAG1 or NOTCH2 mutations is possible. How to Cite this Article Pubmed Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . SRP. 2019; 10(1): 173-178. doi:10.5530/srp.2019.1.32 Web Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . http://www.sysrevpharm.org/?mno=302644894 [Access: March 29, 2021]. doi:10.5530/srp.2019.1.32 AMA (American Medical Association) Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . SRP. 2019; 10(1): 173-178. doi:10.5530/srp.2019.1.32 Vancouver/ICMJE Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . SRP. (2019), [cited March 29, 2021]; 10(1): 173-178. doi:10.5530/srp.2019.1.32 Harvard Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen (2019) of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . SRP, 10 (1), 173-178. doi:10.5530/srp.2019.1.32 Turabian Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. 2019. of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam Reviews in Pharmacy, 10 (1), 173-178. doi:10.5530/srp.2019.1.32 Chicago Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. Ratio of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . Systematic Reviews in Pharmacy 10 (2019), 173-178. doi:10.5530/srp.2019.1.32 MLA (The Modern Language Association) Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen. Ratio of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam . Systematic Reviews in Pharmacy 10.1 (2019), 173-178. Print. doi:10.5530/srp.2019.1.32 APA (American Psychological Association) Style Tram Van Ta, Tuan Anh Nguyen, Truong Viet Nguyen (2019) of JAG1 and NOTCH2 gene mutation characteristics in children with alagille syndrome at Children’s hospital 1 in Ho Chi Minh city, Vietnam Reviews in Pharmacy, 10 (1), 173-178. doi:10.5530/srp.2019.1.32

Long-Term Outcomes After Living-Donor Liver Transplantation for Alagille Syndrome: A Single Center 20-Year Experience in Japan

Alagille syndrome (arteriohepatic dysplasia) is a congenital disorder that can affect the liver, heart, eye, skeleton, and facial appearance.1,,2 It is associated with bile duct paucity and is an important cause of neonatal jaundice and cholestasis in older children.3 The most common cardiac malformation associated with Alagille syndrome is peripheral pulmonary stenosis.4 This syndrome has an autosomal dominant inheritance with variable penetrance, although sporadic cases are common.3 We present two children with sporadic Alagille syndrome who also suffered from moyamoya syndrome, a rare idiopathic intracranial vasculopathy. We hypothesize that this cerebrovascular abnormality may be part of a spectrum of vascular disease that can occur in Alagille syndrome. ### Case 1 A 2-month-old Caucasian girl was diagnosed with Alagille syndrome when she presented with jaundice, pruritis, and failure to thrive. A liver biopsy demonstrated a paucity of bile ducts. Echocardiography revealed pulmonary valvular and pulmonary artery stenosis with right ventricular hypertrophy. Other characteristic features of Alagille syndrome included posterior embryotoxon on eye examination (thickened Schwalbe's ring in the anterior chamber) and butterfly vertebrae (T4 and T7) on spine films. At 1 year of age, the patient underwent a balloon angioplasty of the left pulmonary artery because of severe stenosis. Postoperatively, she was noted to have right arm and leg weakness. Head computed tomography (CT) performed the following day showed decreased attenuation of periventricular white matter in the left frontal lobe. It was thought that she had had an embolic ischemic event affecting the left hemisphere. She regained good function of the right side within weeks. At 21 months of age, the patient developed sudden weakness of the right arm. Magnetic resonance imaging (MRI) demonstrated increased T2-weighted signal intensities in the cortical gyri of the left frontal and parietal lobes associated with enlargement of the left lateral ventricle (Fig …

Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

Reloading Against Rare Liver Diseases

Background: Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF). Coarctation of aorta (CoA), renal and intracranial arteries are commonly involved vessels in Alagille syndrome. We present two cases with rare cardiovascular manifestations of Alagille syndrome. Case description: Case 1: A 25-year-old female with a history of Alagille syndrome presented to the cardiologist office for progressive exertional dyspnoea, orthopnoea, and palpitations. She was tachycardiac on examination and had an apical diastolic rumble. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 60% and parachute mitral valve (PMV) with severe mitral stenosis. A transoesophageal echocardiogram (TOE) showed insertion of chordae into the anterolateral papillary muscle, severe mitral stenosis with a valve area of 0.7 cm. She was referred to a congenital heart disease specialist and underwent robotic mitral valve replacement with improvement in her symptoms. Case 2: A 27-year-old female with known Alagille syndrome and resistant hypertension presented to the cardiologist office due to progressive exertional dyspnoea for a year. She was hypertensive and had a new 2/6 systolic ejection murmur along the left upper sternal border. TTE revealed an LVEF of 60% and pulmonary artery pressure of 19 mmHg. A CoA was suspected distal to the left subclavian artery due to a peak gradient of 38 mmHg. Cardiac magnetic resonance (CMR) imaging ruled out CoA, and diffuse narrowing of the descending thoracic aorta measuring 13–14 mm in diameter was noted. The patient was referred to a congenital heart disease specialist for further management. Conclusion: PMV presenting as mitral stenosis and mid-aortic syndrome are not commonly described anomalies in association with Alagille syndrome. TTE, TOE and CMR played a key role in diagnosis and management of these patients.

Alagille syndrome (AGS), also known as arteriohepatic dysplasia, is an autosomal dominant disorder characterised by a paucity of interlobular bile ducts and chronic cholestasis, cardiac and vascular dysfunction, skeletal and ocular abnormalities and a characteristic facial appearance. Most cases of AGS in patients harbour mutations in either the JAGGED‐1 ( JAG1 ) or Notch2 receptor ( NOTCH2 ) gene. The JAG1 gene encodes a ligand for the Notch receptor. The Notch signalling network controls mammalian cell fate during embryonic development and also dictates several cell phenotypes in adult cells. The majority of JAG1 mutations seen in AGS patients are null alleles, suggesting JAG1 haploinsufficiency as a primary cause of this disorder. Key Concepts: Alagille syndrome is an autosomal dominant disorder with variable expression. Alagille syndrome and associated abnormalities include those of the liver, heart, eye, skeleton and kidneys and characteristic facial features. Mild‐to‐moderate mental retardation also may be present. Alagille syndrome is most often caused by a mutation, or defect, in the JAGGED1 (JAG1) or NOTCH2 receptor gene. Alagille syndrome has been mapped to the 20p12‐jagged‐1 locus, JAG1, which encodes a ligand critical to the NOTCH gene–signalling cascade that is important in fetal development. Notch signalling has been found to regulate formation of three‐dimensional intrahepatic biliary architecture in murine models and vascular cell phenotype during development. A minority (6–7%) of patients have complete deletion of JAG1, and approximately 15–50% of mutations are spontaneous. Deaths in people with Alagille syndrome are most often caused by liver failure, heart problems and blood vessel abnormalities.

Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a rare autosomal dominant genetic disorder caused by mutations in the Notch signalling pathway. The Notch pathway controls mammalian cell fate during embryonic development but also dictates several cell phenotypes in adult cells. The most common mutations affect the Notch ligand, JAG1 (ALGS type 1) or the NOTCH2 receptor (ALGS type 2) genes, and have a significant impact on multiple organ systems. ALGS primarily affects the liver, heart, skeleton, eye, face and kidney. Using animal models, loss‐of‐function mutations in JAG1 reveal that JAG‐1 haploinsufficiency promotes disease phenotypes in most target tissues. Expression and conditional gene knockout studies of JAG1 have further correlated with tissue‐specific disease phenotypes and have provided significant insight into disease pathogenesis. The majority of JAG1 mutations present in ALGS patients are null alleles, suggesting that JAG1 haploinsufficiency is the primary cause of this disorder in humans. Key Concepts Alagille syndrome is an autosomal dominant disorder with variable expression. Alagille syndrome and associated abnormalities include those of the liver, heart, eye, skeleton and kidneys and characteristic facial features. Mild‐to‐moderate mental retardation may also be present. Alagille syndrome is most often caused by a mutation, or defect, in the JAGGED1 (JAG1) or NOTCH2 receptor gene. Alagille syndrome has been mapped to the 20p12‐jagged‐1 locus, JAG1, which encodes a ligand critical to the NOTCH gene‐signalling cascade that is important in foetal development. Notch signalling has been found to regulate formation of three‐dimensional intrahepatic biliary architecture in murine models and vascular cell phenotype during development. A minority (6–7%) of patients have complete deletion of JAG1, and approximately 15–50% of mutations are spontaneous. Deaths in people with Alagille syndrome are most often caused by liver failure, heart problems and blood vessel abnormalities. Therapy is focused on the consequences of liver disease, as well as the surgical and medical treatment of congenital heart defects.

Alagille Syndrome (OMIM 118450) is a multisystem developmental disorder inherited in an autosomal dominant pattern with variable expression. It commonly manifests in children with early cholestatic jaundice due to paucity of interlobular biliary ducts. Renal involvement is less common but can take various forms including renovascular disease, renal agenesis or hypoplasia, cystic renal disease, mesangiolipidosis, tubulointerstitial nephritis and renal tubular acidosis. We describe a family of Alagille syndrome with JAG 1 mutation running through at least two generations, affecting four members with variable phenotypic expressions and disease severity. Alagille syndrome should be considered in the differential diagnosis of adults with renovascular disease and children with agenesis/dysgenesis of kidney and reflux nephropathy even in the absence of hepatic disease. Renal transplant can be successful in these patients although living related donation may not be appropriate given the high penetrance and variable expression of this condition. This syndrome may cause symptomatic bradyarrhythmias as described in our series.

Up to 90% of individuals with Alagille syndrome have congenital heart diseases. Peripheral pulmonary artery stenosis (PPS), resulting in right ventricular hypertension and pulmonary flow disparity, is one of the most common abnormalities, yet the hemodynamic effects are ill-defined, and optimal patient management and treatment strategies are not well established. The purpose of this pilot study is to use recently refined computational simulation in the setting of multiple surgical strategies, to examine the influence of pulmonary artery reconstruction on hemodynamics in this population. Based on computed tomography angiography and cardiac catheterization data, preoperative pulmonary artery models were constructed for 4 patients with Alagille syndrome with PPS (all male, age range: 0.6-2.9 years), and flow simulations with deformable walls were performed. Surgeon directed virtual surgery, mimicking the surgical procedure, was then performed to derive postoperative models. Postoperative simulation-derived hemodynamics and blood flow distribution were then compared with the clinical results. Simulations confirmed substantial resistance, resulting from preoperative severe ostial stenoses, and the use of newly developed adaptive outflow boundary conditions led to excellent agreement with in vivo measurements. Relief of PPS decreased pulmonary artery pressures and improved pulmonary flow distribution both in vivo and in silico with good correlation. Using adaptive outflow boundary conditions, computational simulations can estimate postoperative overall pulmonary flow distribution in patients with Alagille syndrome after pulmonary artery reconstruction. Obstruction relief along with pulmonary artery vasodilation determines postoperative pulmonary flow distribution and newer methods can incorporate these physiologic changes. Evolving blood flow simulations may be useful in surgical or transcatheter planning and in understanding the complex interplay among various obstructions in patients with peripheral pulmonary stenosis.

Ultrasonography evaluation of infants with Alagille syndrome: In comparison with biliary atresia and neonatal hepatitis

Alagille syndrome is an autosomal recessive disorder with multisystemic involvement. Patients with Alagille syndrome have many accompanying anomalies such as atypical facial appearance, posterior embryotoxon, butterfly vertebra, cardiac anomalies, and biliary problems. Liver and heart complications can determine the mortality and morbidity of patients with Alagille syndrome. The scarcity of intrahepatic bile ducts leads to cholestatic liver damage. In the heart, although the disease most commonly causes peripheral pulmonary stenosis, patients can present with various structural heart diseases. These cardiac anomalies make intraoperative and postoperative management difficult in patients who need liver transplant. Here, we present 10 cases of liver transplant due to Alagille syndrome. From 1988 to the present, our center performed 724 liver transplants, with 366 being pediatric cases; among these, 10 were due to Alagille syndrome. We retrospectively examined patient morphological findings, cardiac pathology, and perioperative complications. Average weight and age of patients were 11 kg and 4.9 years, respectively. Eight patients had atypical facial appearance, 5 had posterior embryotoxon, and 6 had butterfly vertebra. Portoenterostomy (Kasai procedure) was performed in 3 patients because of suspicion of early biliary atresia. Cardiac pathology was present in 8 patients, with peripheral pulmonary stenosis being the most common (present in 8 patients). One patient had cardiac catheterization, with right ventricular and pulmonary artery pressures measured at 110 and 37 mm Hg, respectively. Two patients required preoperative pulmonary angioplasty. Two patients had double superior vena cava. No complications occurred in any patient during the anhepatic phase with appropriate volume replacement. No patients had early mortality. Cardiac anomalies should be identified in patients with Alagille syndrome to minimize complications before liver transplant. If necessary, cardiac catheterization should be performed for pulmonary stenosis. Peripheral pulmonary stenosis does not constitute an absolute contraindication to liver transplant.

Alagille syndrome (ALGS) is an autosomal dominant disease caused by JAG1 or NOTCH2 mutation. It is diagnosed by the presence of three out of five features: characteristic facies, posterior embryotoxon, peripheral pulmonary stenosis, vertebral defects, and interlobular bile duct paucity. This study aimed to review the prevalence, clinical presentations, diagnosis, treatment, and outcome of patients with ALGS. This is a retrospective review of patients with ALGS at the Pediatric Department, Salmaniya Medical Complex, Bahrain, between August 1994 and October 2022. The diagnosis was based on clinical, laboratory, radiological, histopathological, and genetic findings. Five patients were found to have ALGS. The prevalence of ALGS in Bahrain was 1.04 patients per 100,000 (0.001%). Four were Bahraini and three were females. Median birth weight was 2.3 (2.3-2.5) kg. All patients presented at the time of birth with low birth weight, cholestatic jaundice, clay-colored stool, heart murmur, and dysmorphic facial features. All had congenital heart diseases, two had butterfly vertebrae, and one had posterior embryotoxon. All had elevated liver enzymes and normal abdominal ultrasound. Three had positive hepatobiliary iminodiacetic acid scan and one had bile duct paucity in liver biopsy. Three had intraoperative cholangiogram. Four were positive for JAG1 mutation. All received ursodeoxycholic acid and fat-soluble vitamins. Two required liver transplantation. ALGS is a rare disorder in Bahrain. Diagnosis is challenging as the disease can be associated with or misdiagnosed as biliary atresia. Patients with ALGS are at high risk of morbidity either by unnecessary intraoperative cholangiogram or unavoidable liver transplantation.