Clinical, pathological and genetic characteristics of 17 unrelated children with Alagille Syndrome.

BACKGROUND: Alagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis. METHODS: We retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022. RESULTS: The clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period. CONCLUSIONS: Among children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Functional characterization of 2,832 JAG1 variants supports reclassification for Alagille syndrome and improves guidance for clinical variant interpretation.

Pathogenic variants in the JAG1 gene are a primary cause of the multi-system disorder Alagille syndrome. Although variant detection rates are high for this disease, there is uncertainty associated with the classification of missense variants that leads to reduced diagnostic yield. Consequently, up to 85% of reported JAG1 missense variants have uncertain or conflicting classifications. We generated a library of 2,832 JAG1 nucleotide variants within exons 1-7, a region with a high number of reported missense variants, and designed a high-throughput assay to measure JAG1 membrane expression, a requirement for normal function. After calibration using a set of 175 known or predicted pathogenic and benign variants included within the variant library, 486 variants were characterized as functionally abnormal (n = 277 abnormal and n = 209 likely abnormal), of which 439 (90.3%) were missense. We identified divergent membrane expression occurring at specific residues, indicating that loss of the wild-type residue itself does not drive pathogenicity, a finding supported by structural modeling data and with broad implications for clinical variant classification both for Alagille syndrome and globally across other disease genes. Of 144 uncertain variants reported in patients undergoing clinical or research testing, 27 had functionally abnormal membrane expression, and inclusion of our data resulted in the reclassification of 26 to likely pathogenic. Functional evidence augments the classification of genomic variants, reducing uncertainty and improving diagnostics. Inclusion of this repository of functional evidence during JAG1 variant reclassification will significantly affect resolution of variant pathogenicity, making a critical impact on the molecular diagnosis of Alagille syndrome.

[Alagille syndrome associated to JAG1 gene deletion. An unusual etiology]. / Síndrome de Alagille por deleción del gen JAG1. Una causa poco frecuente.

Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal abnormalities, and distinct facial features. Most cases are due to variants in the JAG1 gene, with only a small percentage involving a complete gene deletion. OBJECTIVE: to contribute to the phenotype delineation and interpretation of a microdeletion not previously described in the literature on chromosome 20. CLINICAL CASE: A 4-month-old female patient was diagnosed with a heart murmur. An echocardiogram revealed pulmonary artery stenosis, which, combined with a prominent forehead observed on physical examination, determined her referral to clinical genetics. Because ALGS was suspected, complementary studies were performed, revealing butterfly vertebras and a genetic panel identified a pathogenic heterozygous deletion, encompassing the entire coding sequence of the JAG1 gene. To rule out a more extensive deletion, a chromosome microarray was performed, confirming a pathogenic microdeletion on chromosome 20 of 378 kb (arr[GRCh37] 20p12.2(10414643_10792802)x1). CONCLUSIONS: A targeted sequencing panel followed by confirmation with a chromosome microarray allowed the identification and delineation of a pathogenic microdeletion not previously reported in the literature, including the complete JAG1 gene in a Chilean patient whose phenotype is consistent with ALGS.

Generation of an Alagille Syndrome (ALGS) patient-derived induced pluripotent stem cell line (TRNDi036-A) carrying a heterozygous mutation (p.Cys693*) in the JAG1 gene.

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in JAG1 or less frequently, mutations in NOTCH2. The disease has been difficult to diagnose and treat due to variable expression. The generation of this iPSC line (TRNDi036-A) carrying a heterozygous mutation (p.Cys693*) in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.

Macular atrophy and focal choroidal excavation in a patient with JAG1- related alagille syndrome.

INTRODUCTION: Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS. METHODS: Case report. RESULTS: This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid. CONCLUSION: The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE.

This case report highlights the presence of focal choroidal excavation and unilateral macular atrophy in a patient with Alagille syndrome. The genetic analysis identified a pathogenic variant in the JAG1 gene.

Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia.

BACKGROUND AND AIM: Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS: From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS: Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS: Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.

Hepatoblastoma in a cirrhotic child with Alagille syndrome.

Alagille syndrome (AGS) is a genetic disorder due to mutations in the JAGGED 1 or NOTCH 2 genes leading to multisystemic manifestations. Though these patients are at risk of developing various liver tumours, no cases of hepatoblastoma among young children with cirrhosis in AGS have been reported. We report a male toddler, with cirrhosis due to AGS who developed a hepatoblastoma. He underwent a liver transplant for decompensated chronic liver disease with marked pruritus, very high alpha-fetoprotein levels and malignant liver lesions on positron emission tomography CT. His explant histology revealed a paucity of bile ducts and liver lesions turned out to be hepatoblastoma for which he received postoperative chemotherapy. The genetic testing sent before transplantation confirmed the clinical diagnosis of AGS. Hepatoblastoma should be suspected in any child with AGS presenting with a right upper quadrant mass even in the setting of chronic liver disease.

Jagged-mediated development and disease: Mechanistic insights and therapeutic implications for Alagille syndrome.

Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.

Novel JAG1 variants leading to Alagille syndrome in two Chinese cases.

Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic expression of ALGS can lead to challenges in accurately diagnosing affected infants, potentially resulting in misdiagnoses or underdiagnoses. This study highlights novel JAG1 gene mutations in two cases of ALGS. The first case with a novel p.Pro325Leufs*87 variant was diagnosed at 2 months of age and exhibited a favorable prognosis and an unexpected manifestation of congenital hypothyroidism. Before the age of 2, the second patient was incorrectly diagnosed with liver structural abnormalities, necessitating extensive treatment. In addition, he exhibited delays in language acquisition that may have been a result of SNAP25 haploinsufficiency. The identification of ALGS remains challenging, highlighting the importance of early detection and genetic testing for effective patient management. The variant p.Pro325Leufs*87 is distinct from reported variants linked to congenital hypothyroidism in ALGS patients, thereby further confirming the clinical and genetic complexity of ALGS. This emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.

Analysis of a novel JAG1 variant and clinical phenotype in a family affected with Alagille syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a pedigree affected with Alagille syndrome (ALGS).@*METHODS@#Targeted capture and next generation sequencing was carried out for the proband. Candidate variants were verified by Sanger sequencing among his family members. Their pathogenicity of the variant was predicted with bioinformatic analysis. Clinical characteristics and genotype-phenotype correlation were analyzed.@*RESULTS@#The proband, his elder sister and mother were found to carry a heterozygous c.1270dupG (p.Ala424Glyfs*5) variant of the JAG1 gene, which may lead to premature termination of translation and a truncated protein with loss of function. The variant was unreported previously. The phenotypes of the proband (cholestasis, pulmonary artery stenosis and peculiar faces) have differed from those of his elder sister (cholestasis with pruritus, posterior embryonic ring of cornea) and mother (with no clinical manifestation). Cholestasis and peculiar face of the proband became insignificant with age.@*CONCLUSION@#The c.1270dupG (p.Ala424Glyfs*5) variant of the JAG1 gene probably underlay the ALGS in this pedigree with incomplete penetrance.

Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis / 中国当代儿科杂志

OBJECTIVE@#To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis.@*METHODS@#The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family.@*RESULTS@#Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including @*CONCLUSIONS@#The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

A novel JAG1 mutation causing Alagille syndrome presenting with giant hepatic nodules and discordant phenotype in monozygotic twins

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Síndrome de Alagille / Alagille syndrome

Resumen Introducción: El síndrome de Alagille es una enfermedad con múltiples afectaciones, es autosómica dominante, con expresividad variable. Se identifica por manifestaciones hepáticas, vertebrales, cardiacas, oculares y dismorfia facial. Objetivo: Reportar un caso de S. de Alagille con afectación hepática, que debuta con hemorragia de vías digestivas altas. Materiales y métodos: Reporte de caso clínico confrontando con artículos de revisiones de temas en búsqueda electrónica en bases de datos de RIMA, MEDLINE, PUBMED, MEDSCAPE, de 1993-2018. Resultado: Paciente de 2 años, con diagnóstico tardío de enfermedad hepática, con progresión a cirrosis y hallazgos al examen físico que confirman Síndrome de Alagille. Se confirma el diagnóstico molecular coincidiendo con el principal hallazgo genético con anomalías asociadas al gen Jagged 1 (JAG1) localizado en el cromosoma 20 y el NOTCH2 del cromosoma 1. Conclusiones: Es de gran importancia resaltar esta patología infrecuente la cual representa un reto diagnóstico, debe tenerse en cuenta la múltiple afectación orgánica por lo cual es fundamental un manejo interdisciplinario

Abstract Introduction: Alagille syndrome is a disease with multiple impairments, is autosomal dominant with variable expressivity. It is identified by manifestations of vertebral, liver, heart, eye and facial dysmorphia. Objective: Report a case of Alagille S. with hepatic involvement, debuting with hemorrhage of upper digestive tract. Materials and methods: Clinical case report confronting articles reviewing subjects in electronic search in RIMA databases, MEDLINE, PUBMED, MEDSCAPE, from 1993-2018. Result: 2 year old patient, with late diagnosis of liver disease, with progression to cirrhosis and physical exam findings that confirm Alagille Syndrome. Confirmed the diagnostic molecular coinciding with the main genetic finding which are anomalies associated with the gene Jagged 1 (JAG1) located on chromosome 20 and the NOTCH2 of chromosome 1. Conclusions: It is important to highlight this uncommon disease which poses a diagnostic challenge, multiple organic involvement must be taken into account by which an interdisciplinary management is essential.

Síndrome de Alagille con fenotipo atípico diagnosticado por estudio molecular: mutación no descrita en JAG1 / Alagille syndrome with atypical phenotype diagnosed by molecular tests: unreported JAG1 mutation

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Síndrome de Alagille / Alagille syndrome

El síndrome de Alagille es un trastorno genético cuya manifestación fundamental es una colestasis crónica producida por una hipoplasia de las vías biliares intrahepáticas, y se asocia a malformaciones congénitas cardiacas, renales y esqueléticas en pacientes con un fenotipo peculiar. Tiene una frecuencia de aparición de 1 por cada 100 000 nacidos vivos. La lesión histológica está dada por una reducción en la relación entre el número de conductos biliares y el de los espacios porta. Tiene una mortalidad global de un 20 por ciento, y los pacientes pueden llegar a necesitar transplante hepático para su supervivencia. Se describe un paciente de 6 años de edad, femenina, que ingresa a los 23 días de nacida en el Hospital Pediátrico Dr. Eduardo Agramonte Piña por bronconeumonía, pero durante su estancia en el hospital se detecta síndrome colestásico dado por íctero y acolia, además de estenosis pulmonar y facies característica. Se realiza biopsia hepática compatible con síndrome de Alagille. El caso fue evaluado y se diagnostica la enfermedad por la presencia de criterios diagnósticos. Evoluciona de forma estable, con seguimiento por consulta externa hasta los 6 años, cuando ingresa en el Hospital Pediátrico William Soler para transplante hepático(AU)

Alagille syndrome is a genetic disorder and its main manifestation is chronic cholestasis caused by intrahepatic bile duct hypoplasia. It is associated with cardiac, renal and skeletal congenital malformations with peculiar phenotypes. It can occur in one per 100 000 livebirths. The histological lesions are caused by a reduction of the ratio of the number of bile ducts and the number of porta spaces. The global mortality rate of the disease is 20 percent and the patients may need some hepatic transplantation for survival. Here is the case of a 6 years-old girl who was admitted to Dr Eduardo Agramonte Piña hospital when she was 23-days-old because she had bronchopneumonia, but during her stay at hospital, she was detected a cholestatic syndrome with jaundice and acholia in addition to pulmonary stenosis and characteristic facies. A hepatic biopsy was performed. On the basis of some diagnostic criteria, the case was evaluated and diagnosed with this disease. Her progression was stable and she was followed-up until she was 6 years of age when she finally was admitted to William Soler hospital for liver transplantation(AU)

Síndrome de Alagille experiencia clínica de catorce casos en Medellín, Colombia / Alagille syndrome, clinical experience of fourteen cases in Medellin, Colombia

Introducción: El Síndrome de Alagille corresponde a una alteración autosómica dominante con expresión variable. Se caracteriza por colestasis crónica con escasez de los conductos biliares interlobulares asociada a alteraciones cardiovasculares, oftálmicas, sistema esquelético, riñones y facies característica. Su distribución es mundial con frecuencia de 1 por cada 100000 nacidos vivos. Objetivo: Describir las características clínicas, la evolución y la sobrevida de catorce pacientes, con diagnóstico de Síndrome de Alagille atendidos en un período de 16 años en Medellín, Colombia. Materiales y métodos: Es un trabajo observacional descriptivo de reporte de casos de los hallazgos morfológicos y la evolución de los pacientes con diagnóstico de Síndrome de Alagille. Resultados: Grupo compuesto por ocho niños y seis niñas, con edades entre los dos meses y los diez años al momento de diagnóstico. El síndrome completo se presentó en 28%. Los hallazgos más frecuentes, estenosis valvular de la arteria pulmonar y la alteración vertebral se presentaron en el 79%. Tres pacientes 21%, fallecieron, uno de ellos después de recibir trasplante hepático. De los once sobrevivientes dos niñas fueron sometidas a trasplante y se encuentran en buenas condiciones. Los nueve restantes padecen hepatopatía colestásica crónica y reciben tratamiento médico. Conclusión: El Síndrome de Alagille se debe tener en cuenta en el diagnóstico de colestasis crónica infantil. Para establecer la distribución y frecuencia de esta enfermedad en nuestro país es necesario desarrollar investigaciones que idealmente incluyan el estudio de la mutación genética en los pacientes y su familia cercana.

Introduction: The Alagille Syndrome is an autosomic dominant disorder with variable expression. Chronic cholestasis, characteristic facial appearance and abnormalities heart, skeleton, eye, kydnes with hypoplasia of the biliary ducts. Initial description in France, with mundial distribution her frecuence is 1/100000. Objective: To describe the clinical characteristic and evolutions of fourteen patients with diagnosis Alagille Syndrome in Medellín Colombia. Materials and methods: Descriptive retrospective study with variables obtained from clinical records of patients with diagnosis Alagille Syndrome. Results: Eight boys and six girls. The age at diagnosis varied two months at nine years. Complete syndrome was present in 28%. The most frecuent alterations were valvular stenosis pulmonary artery and failure of anterior vertebral arch fusion (butterfly vertebrae) 79%. The clinical evolution was variable, death occurred in three patients 21%, one girl post liver transplantation. Nine children had chronic hepatopathy controlled with medical treatment and two girls had liver transplantation with satisfactory evolution. Conclusions: In Colombia, the poblational incidence is not defined it is necessary to know the distribution of syndrome at future study.

Colestasis: enfoque actual / Cholestasis: current approach

La colestasis, tiene incidencia de 1:60-375 ictéricos a las 2 semanas de edad, es potencialmente grave, presentan riesgos inmediatos como coagulopatías por hemorragia severa ante el déficit de la absorción de la vitamina K, y con su diagnóstico precoz, se identifican patologías que tienen tratamiento, incluso, trasplante hepático. Como consecuencia de la colestasis, hay retención de sales biliares, daño celular hepático, y descenso de la bilis a nivel intestinal, que ocasionan mala digestión de grasas y proteínas, con defectos en las vitaminas liposolubles. Existen hepatopatías primariassecundarias a una serie de entidades genéticas y metabólicas, y colestasis secundarias a otros problemas, que en el adulto generan enfermedad hepática. Es necesario establecer protocolos deidentificación del niño con ictericia.

Cholestasis has 1:60-375 incidence of jaundice at 2 weeks of age, are potentially serious, immediateand present risk of severe bleeding coagulopathy to the shortfall in the absorption of vitamin K, andearly diagnosis, identify diseases that are treatable, even liver transplantation.As a result of cholestasis, there is retention of bile salts, liver cell damage and decrease of bile in the intestine, causing poor digestion of fats and protein, with defects in soluble vitamins. There are primaryliver disease secondary to a variety of metabolic and genetic entities, and cholestasis secondary toother problems, generated in the adult liver disease. It is necessary to establish protocols for the identification of children with jaundice.

Características clínicas y moleculares de una familia con síndrome de Alagille / Molecular and clinical characteristics of a family with Alagille syndrome

Fundamento y objetivo: El síndrome de Alagille (SA) se caracteriza por ductopenia biliar y anomalías del corazón, ojos, cara, huesos, riñón y cerebro, junto a una herencia dominante. Las mutaciones del gen Jagged 1 se observan en sujetos con el síndrome completo y/o familiares que tienen pocos o ningún rasgo fenotípico del síndrome. El pronóstico de los pacientes depende de la afectación hepática y cardiovascular. Pacientes y método: Se presentan los casos de una mujer y sus 2 sobrinos (varones) con SA. Se realizó estudio molecular del gen Jagged 1 en los miembros de la familia con síndrome y sin él. Resultados: El estudio molecular detectó mutaciones en la posición 2785+2 del TAAG (intrón 19) del gen Jagged 1 en 3 familiares que tienen el síndrome completo y en otros 2 casos con síndrome parcial. Otros familiares, sin mutación, presentan alguno de los rasgos fenotípicos del síndrome. Conclusiones: Se comentan las formas clínicas del SA en esta familia y la mutación encontrada. El diagnóstico molecular permite realizar un consejo genético

Background and objective: The Alagille syndrome (AS) is characterized by biliary ductopenia and abnormalities of heart, eyes, face, bones, kidneys and brain with a dominant inheritability. Mutations of Jagged 1 gene are observed in individuals with the full syndrome and/or relatives with little or no phenotypic features. Prognosis of patients depends on the hepatic and cardiovascular involvement. Patients and method: We present the cases of a woman and her 2 male nephews with AS. We performed a molecular study of the Jagged 1 gene in family members with and without the syndrome. Results: The molecular study detected mutations in the position 2785+2 of TAAG (intron 19) of the Jagged 1 gene in 3 relatives with the full syndrome and in 2 other members with a partial syndrome. Other relatives, without mutation, have some of the phenotypic features of it. Conclusions: We comment on the clinical forms of AS in this family and the detected mutation. Molecular diagnosis allows to make a genetic counsel

Anestesia en la colestasis intrahepática. Síndrome de Alagille / Anesthesia in intrahepatic cholestasis: Alagille syndrome

Paciente de 42 años, diagnosticada de Síndrome de Alagille en el primer mes de vida. Ingresa en el Servicio de Cirugía General con diagnóstico de hepatocarcinoma de lóbulo derecho, para la realización de hepatectomía derecha. El Síndrome de Alagille, también conocido como Síndrome de escasez de conductos biliares, es una enfermedad genética extremadamente rara, de afectación multiorgánica. La disfunción hepática y cardíaca será fundamental para la evolución y pronóstico de la enfermedad. Un estudio preoperatorio exhaustivo de la función hepática, cardiológico, hematológica y ósea se antoja funda- mental para el manejo de estos pacientes. En el presente trabajo se revisan los principales pun- tos de la actuación anestésica en los pacientes portado- res de este síndrome

A 42-year-old patient, diagnosed with Alagille syndrome when he was 1 month old, was admitted to the general surgery department to undergo right hepatectomy for right lobe carcinoma. Alagille syndrome, also known as biliary duct hypoplasia, is an extremely rare genetic condition with multiorganic implications. Liver and heart dysfunction will play key roles in the course of the disease and its prognosis. An exhaustive preoperative assessment of liver and heart function, blood chemistry and the skeleton will be essential for managing these patients. This article reviews the main principles underlying the anesthetic management of patients with Alagille syndrome

Morbidity in Alagille syndrome in 6 Malaysian children

We retrospectively studied the records of 6 Malaysian children who were diagnosed with Alagille Syndrome (AGS) according to this criteria from January 1999 to January 2001, at the Institute of Paediatrics, Kuala Lumpur Hospital. Four patients (66%) had a positive family history. Thirteen individuals (6 patients and 7 relatives) were diagnosed with AGS in these 5 families. Only 6/13 (46%) of them presented with liver involvement. All 6 patients presented with typical facies and cholestasis (100%). Three (50%) presented with portal hypertension (PHT) with synthetic liver dysfunction (1 died), 1/6 (17%) have PHT and normal synthetic liver function. Two have cleared their jaundice but have biochemical evidence of hepatitis and hepatomegaly, four have congenital heart disease 5/6 posterior embryotoxon, 2/6 butterfly vertebrae, 4/6 hyperlipidaemia and 4/6 failure to thrive. One patient has a Jagged-1 gene disruption at the translocation breakpoint locus 20p12.3 2n = 46,XX,t(12.20) (q22, p12.3). 5/6 (83%) are still alive. Two-thirds of our patients developed chronic liver disease by 3 years of age. Two-thirds of the index patients have a family history. Only 46% of individuals in these families have clinical evidence of liver involvement. Mortality depends on cardiac/renal disease, end-stage liver failure and intercurrent infection.