Alagille Syndrome: An Overview

2017 ◽  
Vol 36 (6) ◽  
pp. 343-347 ◽  
Author(s):  
Dalacy Jesina
Keyword(s):  
Autosomal Dominant ◽  
Pulmonary Stenosis ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Autosomal Dominant Disorder ◽  
Vascular Events ◽  
Variable Expression ◽  
Intrahepatic Bile Ducts ◽  
Improved Outcomes ◽  
Detection And Diagnosis

AbstractAlagille syndrome (AGS) is a highly complex, multisystem, autosomal dominant disorder that is caused by a defect in the Notch signaling pathway. This syndrome mainly affects the liver, causing significant cholestasis, which is caused by a paucity of intrahepatic bile ducts. There can be cardiac involvement, including, but not limited to, pulmonary stenosis and tetralogy of Fallot. Patients can also present with butterfly vertebra, ocular issues, and vascular events. Because this syndrome follows an autosomal dominant inheritance, it can have variable expression even in the same family line. For infants in the NICU who have a cardiac defect and persistent hyperbilirubinemia after two weeks of age, genetic testing for AGS should be considered. Early detection and diagnosis can lead to improved outcomes. In this discussion of AGS, the clinical features as well as management are discussed.

scholarly journals A Novel c.91dupG JAG1 Gene Mutation Is Associated with Early Onset and Severe Alagille Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Alejandra del Pilar Reyes-de la Rosa ◽  
Gustavo Varela-Fascinetto ◽  
Constanza García-Delgado ◽  
Edgar Ricardo Vázquez-Martínez ◽  
Pedro Valencia-Mayoral ◽  
...  
Keyword(s):  
De Novo ◽  
Pulmonary Stenosis ◽  
Gene Mutations ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Autosomal Dominant Disorder ◽  
Intrahepatic Bile Ducts ◽  
Chronic Cholestasis

Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome.

scholarly journals ALAGILLE SYNDROME AS A CHALLENGING CLINICAL CASE IN PEDIATRIC PRACTICE (case report)

2017 ◽  
Vol 4 (2) ◽  
pp. 83-85
Author(s):  
Nigar Hajiyeva
Keyword(s):  
Clinical Case ◽  
Spontaneous Mutation ◽  
Pulmonary Stenosis ◽  
Alagille Syndrome ◽  
Final Diagnosis ◽  
Autosomal Dominant Disorder ◽  
Chronic Cholestasis ◽  
Characteristic Features ◽  
Prolonged Jaundice ◽  
Peripheral Pulmonary Stenosis

Hajiyeva N.A.Alagille syndrome is a multisystem, highly variable, autosomal dominant disorder, which can be triggered by spontaneous mutation. This disease primarily affects the liver (chronic cholestasis), heart (most often peripheral pulmonary stenosis), eyes (posterior embryotoxon), face (characteristic features), and skeleton (butterfly vertebrae). The paper presents the clinical case of prolonged jaundice with an increased liver enzymes in infant and no final diagnosis for a long time.KeyWords: Alagille syndrome, chronic cholestasis, ursodeoxycholic acid СИНДРОМ АЛАЖІЛЯ, ЯК СКЛАДНИЙ КЛІНІЧНИЙ ПРИКЛАД З ПЕДІАТРІЧНОЇ ПРАКТИКИ (клінічний випадок)Хаджієва Н.А.Синдром Алажіля є мультисистемним варіабельним аутосомно-домінантним розладом, який є наслідком спонтанної мутації. Це захворювання перед усім уражує печінку (хронічний холестаз), серце (найчастіше периферичний стеноз легеневої артерії), очі (задні ембріотоксони), обличчя (характерні ознаки) і скелет (хребці у вигляді метеликів). В публікації представлений клінічний випадок тривалої жовтяниці з підвищеням печінкових ферментів у дитини раннього віку, у якої протягом тривалого часу неможливо було встановти клінічний діагноз.Ключові слова: синдром Алажіля, хронічний холестаз, урсодеоксихолєва кислота СИНДРОМ АЛАЖИЛЯ КАК СЛОЖНЫЙ КЛИНИЧЕСКИЙ ПРИМЕР ИЗ ПЕДИАТРИЧЕСКОЙ ПРАКТИКИ (клинический случай)Хаджиева Н.А.Синдром Алажиля является мультисистемным вариабельным аутосомно-доминантным расстройством, которое является следствием спонтанной мутации. Это заболевание прежде всего поражает печень (хронический холестаз), сердце (чаще всего периферический стеноз легочной артерии), глаза (задний эмбриотоксон), лицо (характерные признаки) и скелет (позвонки в виде бабочек). В публикации представлен клинический случай длительной желтухи с повышением печеночных ферментов у ребенка раннего возраста, у которого в течение длительного времени невозможно было установить клинический диагноз.Ключевые слова: синдром Алажиля, хронический холестаз, урсодеоксихолевая кислота

scholarly journals Novel mutations in NOTCH2 gene in infants with neonatal cholestasis

2019 ◽  
Vol 11 (3) ◽  
Author(s):  
Eliana Shaul ◽  
Debora Kogan-Liberman ◽  
Stephanie Schuckalo ◽  
Dominique Jan ◽  
Michelle Ewart ◽  
...  
Keyword(s):  
Case Series ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Clinical Approach ◽  
Neonatal Cholestasis ◽  
Retrospective Case ◽  
Variants Of Unknown Significance ◽  
Intrahepatic Bile Ducts ◽  
Sorting Intolerant From Tolerant ◽  
Unknown Significance

One cause of neonatal cholestasis (NC) is paucity of intrahepatic bile ducts which can be associated with Alagille syndrome or non- syndromic. Alagille syndrome is caused by autosomal dominant mutations in the Notch signaling pathway ligand Jagged1 in 94% of patients and mutations in the NOTCH2 receptor in <1% of patients. This is a retrospective case series studying infants with neonatal cholestasis found to have variants of unknown significance (VOUS) in NOTCH2. Sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen) were utilized to predict a damaging effect. Five infants with NC without other features of Alagille syndrome were found to have one copy of a VOUS in NOTCH2, predicted to be damaging by SIFT and PolyPhen. Our cases support the notion that NOTCH2 mutations may result in hypoplastic biliary system. Further characterization of these variants is important to assist with our clinical approach to NC.

scholarly journals In silico analysis of CDC73 gene revealing 11 novel SNPs associated with Jaw Tumor Syndrome

2019 ◽  
Author(s):  
Abdelrahman H. Abdelmoneim ◽  
Alaa I. Mohammed ◽  
Esraa O. Gadim ◽  
Mayada A.Mohammed ◽  
Sara H. Hamza ◽  
...  
Keyword(s):  
In Silico ◽  
Autosomal Dominant ◽  
In Silico Analysis ◽  
Autosomal Dominant Disorder ◽  
Variable Expression ◽  
Back Ground ◽  
And Function ◽  
Molecular Aberrations ◽  
The Impact ◽  
Silico Analysis

AbstractBack groundhyperparathyroidism-jaw tumor (HPT-JT) is an autosomal dominant disorder with variable expression, with an estimated prevalence of 6.7 per 1,000 population. Genetic testing for predisposing CDC73 (HRPT2) mutations has been an important clinical advance, aimed at early detection and/or treatment to prevent advanced disease. The aim of this study is to assess the effect of SNPs on CDC73 structure and function using different bioinformatics tools.MethodComputational analysis using eight different in-silico tools including SIFT, PROVEAN, PolyPhen-2, SNAP2, PhD-SNP, SNPs&GO, PMut and Imutant were used to identify the impact on the structure and/or function of CDC73 gene that might be causing jaw tumour.ResultsFrom (733) SNPs identified in the CDC73 gene we found that only Eleven were deleterious to the function and structure of protein and expected to cause syndrome.ConclusionEleven substantial genetic/molecular aberrations in CDC73 gene were identified that could serve as actionable targets for chemotherapeutic intervention in patients whose disease is no longer surgically curable.

scholarly journals Alagille Syndrome: Resolution of Xanthomas

1995 ◽  
Vol 9 (4) ◽  
pp. 187-190
Author(s):  
NJ Leonard ◽  
V Dias ◽  
HG Parsons
Keyword(s):  
Pulmonary Stenosis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Alagille Syndrome ◽  
Total Serum ◽  
Total Serum Cholesterol ◽  
Autosomal Dominant Disorder ◽  
Chronic Cholestasis ◽  
Peripheral Pulmonary Stenosis

Alagille syndrome is a rare autosomal dominant disorder characterized by chronic cholestasis due to paucity of intrahepatic biliary ducts, characteristic facies, peripheral pulmonary stenosis, ocular posterior embryotoxon and skeletal abnormalities. Very little information is available on the cholestatic, lipid and lipoprotein profiles in individuals with Alagille syndrome. The course of xanthomatosis and the lipid-lipoprotein profile of a 15-year-old male with incomplete Alagille syndrome with marked xanthomatosis and extremely elevated cholesterols secondary to cholestasis is reported. He showed gradual resolution of xanthomas beginning at age 12 years with a concurrent reduction in his total serum cholesterol. The lipid studies showed that the majority of cholesterol was found in low density lipoprotein (LDL) with lesser amounts in lipoprotein (Lp)-X, a lipoprotein precursor complex seen in patients with cholestasis, and high density lipoprotein (HDL). With resolution of xanthomas, LDL and Lp-X decreased while HDL-cholesterol and apolipoprotein (Apo) A-I increased. Gamma glutamyltransferase and bilirubin decreased but remained 15- and threefold elevated, respectively.

scholarly journals Alagille syndrome: Review of 14 patients

2017 ◽  
Vol 41 (1) ◽  
pp. 47
Author(s):  
Purnamawati S. Pujiarto ◽  
Arnold L. Smith
Keyword(s):  
Liver Biopsy ◽  
Autosomal Dominant ◽  
Diagnostic Testing ◽  
Alagille Syndrome ◽  
Poor Quality ◽  
Autosomal Dominant Disorder ◽  
Hemorrhagic Pneumonia ◽  
Group 2 ◽  
Group 1

Alagille syndrome (AGS) Is a common form of familial intrahepatic choleslasis, an autosomal dominant disorder due to defects in Jagged1 gene. It Is characterized by at least 3 of 5 mator features. We reviewed two groups of patients with AGS. Group 1 comprised 12 AGS patients, retrospectively studied (1995-1996), in the Gastroenterology Department, Royal Children's Hospital, Melbourne. Group 2 comprised 2 AGS patients, prospectively studied since 1999, in The Pediatric Hepatology Division, Cipto Mangunkusumo Hospital, Jakarta. Prolonged cholestasis is the most common feature at presentation (12 patients). All these 12 subjects developed pruritus and xanthoma of varying degree. Osteopenia occured in 6 patients, 2 patients experienced fractures. AGS facies was noted In aH 14 subjects. Heart anomaty was found in 10 patients, vertebral anomaly in 6 patients, and posterior embryotoxin in 10 patients. Common additional features were growth and mental retardation in 10 and 8 patients, respectively. Liver biopsy was able to confirm the diagnosis as young as age 2 months. Death occurred in 2 patients due to liver failure and hemorrhagic pneumonia. Liver transplant was done in 1 patient due to poor quality of life (severe pruritus, xanthoma, recurrent fractures). Affected family members were strongly presumed in 8 patients. In conclusion, AGS should be considered in babies with chronic Intrahepatic cholestasls, especially it associated with pruritus. Liver biopsy Is the most sensitive diagnostic testing which will prevent unnecessary surgical intervention due to biliary atresia mimicry.

Singleton-Merten syndrome: An autosomal dominant disorder with variable expression

2013 ◽  
Vol 161 (2) ◽  
pp. 360-370 ◽  
Author(s):  
Annette Feigenbaum ◽  
Christine Müller ◽  
Christopher Yale ◽  
Johannes Kleinheinz ◽  
Peter Jezewski ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Autosomal Dominant Disorder ◽  
Variable Expression

scholarly journals In silico analysis of CDC73 gene revealing 11 novel SNPs with possible association to Hyperparathyroidism-Jaw Tumor syndrome

2020 ◽  
Vol 4 (2) ◽  
pp. 67-81
Author(s):  
Abdelrahman H. Abdelmoneim ◽  
Alaa I. Mohammed ◽  
Esraa O. Gadim ◽  
Mayada Alhibir Mohammed ◽  
Sara H. Hamza ◽  
...  
Keyword(s):  
In Silico ◽  
Autosomal Dominant ◽  
In Silico Analysis ◽  
Autosomal Dominant Disorder ◽  
Variable Expression ◽  
Project Hope ◽  
Molecular Aberrations ◽  
Structural Levels ◽  
The Impact ◽  
Silico Analysis

AbstractHyperparathyroidism-Jaw Tumor (HPT-JT) is an autosomal dominant disorder with variable expression, with an estimated prevalence of 6.7 per 1,000 population. Genetic testing for predisposing CDC73 (HRPT2) mutations has been an important clinical advance, aimed at early detection and/or treatment to prevent advanced disease. The aim of this study is to assess the most deleterious SNPs mutations on CDC73 gene and to predict their influence on the functional and structural levels using different bioinformatics tools. Method: Computational analysis using twelve different in-silico tools including SIFT, PROVEAN, PolyPhen-2, SNAP2, PhD-SNP, SNPs&GO, P-Mut, I-Mutant ,Project Hope, Chimera, COSMIC and dbSNP Short Genetic Variations were used to identify the impact of mutations in CDC73 gene that might be causing jaw tumor. Results: From (733) SNPs identified in the CDC73 gene we found that only Eleven SNPs (G49C, L63P, L64P, D90H, R222G, W231R, P360S, R441C, R441H, R504S and R504H) has deleterious effect on the function and structure of protein and expected to cause the syndrome. Conclusion: Eleven substantial genetic/molecular aberrations in CDC73 gene identified that could serve as diagnostic markers for hyperparathyroidism-jaw tumor (HPT-JT).

scholarly journals Novel Heterozygous Mutations in JAG1 and NOTCH2 Genes in a Neonatal Patient with Alagille Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Alisa Brennan ◽  
Anil Kesavan
Keyword(s):  
Congenital Heart ◽  
Heart Defects ◽  
Alagille Syndrome ◽  
Multiple Organ ◽  
Complex Congenital Heart Disease ◽  
Autosomal Dominant Disorder ◽  
Intrahepatic Bile Ducts ◽  
Organ Systems ◽  
Newborn Girl ◽  
Neonatal Patient

Alagille Syndrome (ALGS) is a rare autosomal dominant disorder that affects multiple organ systems. Cholestasis as a result of a paucity of intrahepatic bile ducts and congenital heart defects are the two most common features of ALGS. We describe a case of ALGS with novel mutations of JAG1 and NOTCH2 genes in a newborn girl with complex congenital heart disease, bilateral dysplastic kidneys, and malrotation with volvulus.

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