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Background

Alagille syndrome is a rare inherited syndrome characterized by a reduction in intrahepatic bile ducts associated with multiple abnormalities in many other organ systems such as the cardiovascular system, skeleton, and kidneys. Recently, the syndrome has been associated with mutations in the JAGGED gene, mapped to chromosome 20.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Alagille-Watson syndrome
Arteriohepatic dysplasia
Syndromic bile duct paucity
INCIDENCE/
PREVALENCE
1/100,000 live births
AGE  
SEX  
GEOGRAPHY  
EPIDEMIOLOGIC ASSOCIATIONS  

 

DISEASE ASSOCIATIONS CHARACTERIZATION
COAGULOPATHY  
Bleeding tendency in children with Alagille syndrome.

Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M.

Service d'Hepatologie pediatrique, Hopital de Bicetre, Le Kremlin Bicetre Cedex, France.
Pediatrics. 2003 Jan;111(1):167-70. Abstract quote  

OBJECTIVE: Spontaneous intracranial bleeding is now a widely recognized complication and cause of mortality in patients with Alagille syndrome. The pathogenesis of intracranial bleeding in these patients remains unclear. The aim of the study was to look for other sites of bleeding in these patients that could suggest a factor of multiorgan morbidity.

METHODS: The records of 174 patients with Alagille syndrome were reviewed, and 38 (22%) patients without liver failure who experienced hemorrhage that led to a drop in hemoglobin level of at least 3 g/dL or to blood transfusion were identified.

RESULTS: In 38 patients, 49 bleeding episodes occurred at a median age of 3.75 years (range: 1 month-27 years). Seventeen patients had 23 episodes of spontaneous bleeding; 21 patients bled during surgery or other medical procedures, and 5 among these 21 patients also had a spontaneous bleeding episode. Nine patients bled at least twice. Median platelets count and prothrombin time were normal. Severe cholestasis existed in 33 patients. One patient has a deletion of the 20p12 region, and 13 of 17 patients studied have a JAGGED1 mutation. Blood transfusion was necessary in 23 patients. Eight patients died secondary to bleeding (4 after surgery, 2 after gastrointestinal bleeding, 1 after needle liver biopsy, and 1 after intracranial bleeding).

CONCLUSION: These results suggest that patients with Alagille syndrome are at special risk for bleeding; this should be taken into account before deciding on an invasive procedure. The mechanism of the bleeding is still unclear; the role of hypercholesterolemia cannot be excluded, but it may be speculated that JAGGED1 signaling abnormalities may impair the hemostatic function.
RENAL ARTERY STENOSIS  
Successful stenting for renal artery stenosis in a patient with Alagille syndrome.

Hirai H, Santo Y, Kogaki S, Kurotobi S, Etani Y, Mushiake S, Nakatsuchi Y, Nakajima S, Ozono K.

Department of Pediatrics, D-5, Developmental Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
Pediatr Nephrol. 2005 Jun;20(6):831-3. Epub 2005 Mar 17. Abstract quote  

A 12-year-old girl with Alagille syndrome manifested severe hypertension caused by renal artery stenosis in a solitary functioning kidney. Percutaneous transluminal angioplasty (PTA) and stenting was performed, but the hypertension persisted.

On the next day, acute renal failure occurred with the administration of angiotensin-converting enzyme inhibitor, and migration of the stent was confirmed by angiography. Thus, a second stent was placed with success.

Since then, the hypertension has been controlled with anti-hypertensive medication, and the renal function has recovered to normal range.

 

PATHOGENESIS CHARACTERIZATION
JAGGED GENE  
Expression of mutant JAGGED1 alleles in patients with Alagille syndrome.

Boyer J, Crosnier C, Driancourt C, Raynaud N, Gonzales M, Hadchouel M, Meunier-Rotival M.

INSERM E00-20, Batiment Gregory Pincus, 80 rue du General Leclerc, 94276, Le Kremlin-Bicetre cedex, France
,
Hum Genet. 2005 May;116(6):445-53. Epub 2005 Mar 17. Abstract quote  

Heterozygous mutations in JAGGED1 (JAG1), encoding a ligand for Notch receptors, have been identified in patients with Alagille syndrome (AGS). These mutations map to the extracellular and transmembrane domains of JAG1, giving rise in 70% cases to a premature termination codon (PTC). Although haploinsufficiency has been hypothesised as the main mechanism of AGS, a dominant negative effect of truncated forms of Serrate/Jagged has been suggested. Only few studies of the mutant mRNAs and proteins from AGS patients have been performed to elucidate the molecular mechanisms of the disease.

To gain insight into the stability of mutant mRNAs, we studied transcripts from five livers and 24 lymphoblastoid cell lines (LCLs) of AGS patients. Mutant JAG1 transcripts were recovered (albeit in different relative amounts) from RNAs with missense mutations (five) or in-frame deletions (two), and from all but two of the 21 with PTCs. In addition, results from LCL RNAs correlated well with results from liver RNAs. Mutant transcripts were also recovered from tissues of a 23-week-old AGS foetus with a PTC mutation. This suggests that most mutant transcripts with PTCs escape nonsense-mediated mRNA decay (NMD) and could lead to the synthesis of soluble forms of JAG1. Production of a truncated protein was indeed observed after transfection of COS cells with a mutant JAG1 cDNA.

In conclusion, mutant JAG1 transcripts are present in LCLs, livers and tissues of AGS patients, whatever the mutation type, and mutant proteins can be produced, suggesting a dominant negative effect of some mutant proteins as another molecular mechanism of AGS.
Twelve novel JAG1 gene mutations in polish Alagille syndrome patients.

Jurkiewicz D, Popowska E, Glaser C, Hansmann I, Krajewska-Walasek M.

Children's Memorial Health Institute, Department of Medical Genetics, Warsaw, Poland.
Hum Mutat. 2005 Mar;25(3):321. Abstract quote  

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities of the liver, heart, eyes, vertebrae, and face. Mutations in the JAG1 (Jagged 1) gene, coding a ligand in the evolutionarily conserved Notch signaling pathway, are responsible for AGS.

Here we present sixteen different JAG1 gene mutations, among them twelve novel, not described previously. Seven frameshift: c. 172_178del7 (p.Ala58fs), c.509delT (p.Leu170fs), c.1197delG (p.Val399fs), c.1485_1486delCT (p.Pro495fs), c.1809_1810insTGGG (p.Lys604fs), c.2122_2125delCAGT (p.Gln708fs), c.2753delT (p.Ile918fs); five nonsense: c.383G>A (p.Trp128X), c.496C>T (p.Glu166X), c.841C>T (p.Gln281X), c.1207C>T (p.Gln403X), c.1603C>T (p.Gln535X); two splice site: c.388-1G>C, c.3048+1_3048+2insG and two missense mutations: c.359T>A (p.Ile120Asn), c.560G>A (p.Cys187Tyr) were found.

Forty percent of the changes were identified in exons 2 and 4, the remaining mutations are distributed along the entire coding sequence of the gene. Seventy-five percent of the mutations lead to creation of premature termination codons. Family studies revealed that the specific mutations were inherited in 3 out of 11 investigated cases. No correlation between genotype and phenotype was observed.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
LABORATORY MARKERS  

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
VARIANTS  
CNS  
Multiple cerebral aneurysms and subarachnoid hemorrhage in a patient with Alagille syndrome.

Schlosser HG, Kerner T, Woiciechowsky C, Benndorf G.

Department of Neurosurgery, Charite, Virchow-Clinic, Humboldt-University of Berlin, Berlin, Germany.
AJNR Am J Neuroradiol. 2004 Sep;25(8):1366-7. Abstract quote  

Although intracranial hemorrhage has frequently been found responsible for mortality in adult patients with Alagille syndrome (AGS), no specific underlying cause has been identified.

We describe the case of severe subarachnoid hemorrhage in a 30-year-old woman harboring five intracranial aneurysms and multiple peripheral vascular anomalies.

To evaluate a possible higher incidence of intracranial aneurysms, a study of the cerebral vasculature in all AGS patients by using noninvasive imaging techniques should be considered.
SKELETAL  

Deficits in size-adjusted bone mass in children with Alagille syndrome.

Olsen IE, Ittenbach RF, Rovner AJ, Leonard MB, Mulberg AE, Stallings VA, Piccoli DA, Zemel BS.

Center for Epidemiology and Biostatistics and Division of Neonatology, Cincinnati Children's Hospital Medical Cente, The University of Cincinnati College of Medicine, Cincinnati, OH, USA.
J Pediatr Gastroenterol Nutr. 2005 Jan;40(1):76-82. Abstract quote  

OBJECTIVES: To describe bone status in children with Alagille syndrome (AGS) and healthy control children adjusted for age, gender and height (HT), and to identify dietary intake and AGS-related factors associated with bone status.

METHODS: Prepubertal children with AGS and healthy controls comparable in age and ethnicity were evaluated. Subjects were > or =4 years of age, prepubertal and had whole body (WB) and/or lumbar spine (LS) dual energy X-ray absorptiometry (DXA) scans of acceptable quality. Anthropometric (weight, HT), diet and AGS-specific data (e.g., coefficient of fat absorption, labs, liver transplantation) were also collected. Bone area (BA), bone mineral content (BMC) and HT were log transformed for best fit. Bone data were analyzed unadjusted, adjusted for gender, age and HT, and as HT-specific z-scores.

RESULTS: AGS and control groups were similar in age, pubertal status and ethnicity. Children with AGS were small-for-age, had decreased BA and BMC-for-age, and decreased WB BA and BMC-for-HT z-scores compared to healthy controls. Prevalence of low BMC-for-HT z-scores (< -2) among AGS subjects was 20% for the WB and 39% for the LS. Bone mineralization was positively related to fat absorption but not dietary intake.

CONCLUSIONS: Children with AGS have deficits in bone size and bone mass relative to body size. Modifiable factors, such as treatment of malabsorption should be explored as an early focus of AGS care to prevent bone fragility.
Alagille syndrome: case report with bilateral radio-ulnar synostosis and a literature review.

Ryan RS, Myckatyn SO, Reid GD, Munk P.

Department of Radiology, Vancouver General Hospital, 899 W 12th Avenue, Vancouver, BC, V5Z 1M9, Canada.
Skeletal Radiol. 2003 Aug;32(8):489-91. Epub 2003 Jun 11. Abstract quote  

We report a case of Alagille syndrome (arteriohepatic dysplasia) with the unusual radiological abnormality of synostosis of the proximal portions of the radius and ulna bilaterally, a manifestation which, to our knowledge, has not previously been described in a specific patient in the English language literature.

We also describe additional features of the syndrome in the same patient and review the published literature on radiological manifestations of this condition.
Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients.

Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS.

Department of Clinical Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
Pediatr Radiol. 2002 Feb;32(2):114-9. Epub 2001 Dec 15. Abstract quote  

BACKGROUND: Vertebral anomalies may help differentiate Alagille syndrome from other causes of chronic cholestasis. We suspect significant under-reporting of vertebral anomalies in children with Alagille syndrome.

OBJECTIVE: To compare the vertebral anomalies in Alagille syndrome with those in patients with chronic cholestasis due to other causes. The accuracy of original radiographic reporting was evaluated.

MATERIALS AND METHODS: Spinal radiographs of 50 patients with Alagille syndrome and 31 non-Alagille syndrome cholestatic patients were evaluated retrospectively by four trained radiologists. The number, site and type of vertebral anomaly were noted. The consensus evaluation was then compared to the original report.

RESULTS: Vertebral anomalies were found in 66% of patients with Alagille syndrome and 9.7% of cholestatic control subjects ( P<0.0005). In the patients with Alagille syndrome, incomplete fusion of the anterior arch, most frequently at the D6-9 level, accounted for 123 of 126 anomalies. Multiple vertebral anomalies occurred in 48% of patients with Alagille syndrome (mean 2.5 anomalies). Vertebral anomalies were misreported in 54% of cases of Alagille syndrome.

CONCLUSIONS: Vertebral anomalies are significantly more common in Alagille syndrome than in chronic cholestasis of other causes and are frequently overlooked. Reporting should be undertaken by a radiologist familiar with the appearance and location of these vertebral anomalies.
SKIN  
Alagille syndrome: cutaneous manifestations in 38 children.

Garcia MA, Ramonet M, Ciocca M, Cabrera H, Lapunzina P, Alvarez E, de Davila MT.

Dermatology Department, Posadas Hospital, Buenos Aires, Argentina.
: Pediatr Dermatol. 2005 Jan-Feb;22(1):11-4. Abstract quote  

The Alagille syndrome is one of the most common inherited disorders causing chronic liver disease during childhood. During the 1990s, 38 children with Alagille syndrome were evaluated at two pediatric centers in Buenos Aires, Argentina. Characteristic clinical, humoral, and cutaneous features were analyzed

. The average age of diagnosis was 29 months old (range of between 2 months and 15 years). Cholestasis was evident in 92% of patients during the neonatal period. Family antecedents related to the syndrome were found in 18.5% of the patients. Peculiar facies developed in 85% of patients. Chronic cholestasis and pruritus were observed in all of the patients and jaundice was evident in 78%.

Eighty-four percent of the patients had heart disease (pulmonary stenosis, intraauricular communication, intraventricular communication), 76% of them showed growth retardation, and vertebrae abnormalities were found in 63%. Embryotoxon appeared in 76% of patients, and renal disturbances in 21%. Eleven children (28%) had xanthomas, in the neck, elbows, palms, helixes, inguinal area, gluteus, and knees. The earliest findings appeared in the first months of life, and the latest at 5 years of age. The xanthomas located in the folds had a stony aspect. Cholesterol levels ranging from 220 to 1600 mg percentage (mg%) were demonstrated in all of the children with xanthomas.

Liver transplantation was performed in seven of the patients (18.4%). Two of them died after this operation. The disappearance of xanthomas after transplantation was remarkable in all of the patients.
Papular umbilicated granuloma annulare in association with Alagille syndrome.

Kibarian MA, Mallory SB, Keating J, Shitabata P.

Department of Dermatology, Washington University School of Medicine, St Louis, Missouri, USA.
Int J Dermatol. 1997 Mar;36(3):207-9.

VASCULAR  
Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.

Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID.

Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pa 19104, USA.

Circulation. 2004 Mar 23;109(11):1354-8. Epub 2004 Mar 1 Abstract quote.  

BACKGROUND: Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations in Jagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS.

METHODS AND RESULTS: Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort.

CONCLUSIONS: The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role for Jagged1 and the Notch signaling pathway in vascular development.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome: Further Evidence Supporting a Lack of Postnatal Bile Duct Branching and Elongation.

Libbrecht L, Spinner NB, Moore EC, Cassiman D, Damme-Lombaerts RV, Roskams T.

From the Departments of *Pathology, daggerHepatology, and double daggerGastrointestinal Pediatrics, University Hospitals of Leuven, Leuven, Belgium; and section signDivision of Human Genetics and Molecular Biology, Department of Pediatrics and Clinical Laboratories, Children's Hospital of Philadelphia, Philadelphia, PA.

Am J Surg Pathol. 2005 Jun;29(6):820-826. Abstract quote  

Alagille syndrome (AGS) is a developmental, multiorgan disease caused by mutations of the Jagged1 gene. The liver is one of the major organs affected in AGS, and the hallmark of liver pathology in AGS is an age-related increase in the proportion of portal tracts that have no bile duct, but without evidence of prominent bile duct damage. The pathogenesis of this bile duct paucity is currently not well understood.

(Immuno)histochemical and molecular analyses were performed on several liver biopsies that were taken during macroscopic examination of the explant liver of a 17-year-old AGS patient. The liver periphery was macroscopically pale and was microscopically characterized by complete absence of bile ducts and presence of severe cholestasis, but there was no ductular reaction. Conversely, the central, hilar portion contained normally developed bile ducts showing no or minimal damage and cholestasis. A missense mutation in the Jagged1 gene was present in both parts of the liver, indicating that mosaicism did not cause this peculiar picture. There was also a hypertrophy of the hepatic arterial branches in the liver periphery.

Together with previous indirect findings, the current study of the explant liver of an AGS patient strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity and cholestasis develops in AGS. Our findings also suggest that anomalies of the intrahepatic arterial branches may be part of AGS in some patients.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
ELECTRON MICROSCOPY  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

 

PROGNOSIS CHARACTERIZATION
MALIGNANCIES  
Hepatocellular carcinoma occurring in alagille syndrome.

Kim B, Park SH, Yang HR, Seo JK, Kim WS, Chi JG.

Department of Pathology, College of Medicine, Seoul National University, Yongon-dong 28, Chongno-gu, Seoul 110-799, South Korea.
Pathol Res Pract. 2005;201(1):55-60. Abstract quote  

Hepatocellular carcinoma only rarely occurs in Alagille syndrome. Here, we report on three cases of hepatocellular carcinoma associated with Alagille syndrome. All three patients were boys and presented with jaundice. In addition, they had the characteristic facial appearance of Alagille syndrome with cardiac, vertebral, and eye anomalies, and all had passed acholic stools from the neonatal period.

Liver biopsies were diagnosed as bile duct paucity, compatible with Alagille syndrome in two cases, but the third case showed marked bile duct proliferation at the initial liver biopsy when 7 months old, which made diagnosis difficult. Eventually, all three cases progressed to biliary cirrhosis and hepatocellular carcinoma, which occurred at 17 months, 4 years, and 7 years, respectively.

Because of the unusual liver histology and early onset of hepatocellular carcinoma, careful clinicopathologic correlations and close monitoring are required for the diagnosis of Alagille syndrome and for the early detection of hepatocellular carcinoma.
SURVIVAL  
Morbidity in Alagille syndrome in 6 Malaysian children.

Lim CB, Choy YS.

Institute of Paediatrics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur.

Med J Malaysia. 2003 Dec;58(5):641-6. Abstract quote  

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.
Outcome of liver disease in children with Alagille syndrome: a study of 163 patients.

Lykavieris P, Hadchouel M, Chardot C, Bernard O.

Service d'Hepatologie Pediatrique, Hopital de Bicetre, 94275 Le Kremlin Bicetre Cedex, France.
Gut. 2001 Sep;49(3):431-5. Abstract quote  

BACKGROUND AND AIMS: Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS).

PATIENTS AND METHODS: We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit.

RESULTS: At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004).

CONCLUSIONS: The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life.
Variable morbidity in alagille syndrome: a review of 43 cases.

Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall TR, McDiarmid SV, Vargas JH.

Division of Pediatric Gastroenterology, University of California Los Angeles Medical Center 90095-1752, USA.
J Pediatr Gastroenterol Nutr. 1999 Oct;29(4):431-7. Abstract quote

BACKGROUND: Alagille syndrome is one of the most common inherited disorders that cause chronic liver disease in children. Early reports suggested a benign course in these patients. Subsequent reports showed significant morbidity and mortality. This study was designed to analyze the long-term clinical course in Alagille syndrome.

METHODS: The records of children with Alagille syndrome seen during a 20-year period were reviewed.

RESULTS: Forty-three patients were identified. Liver disease was diagnosed before 12 months of age in 95%. The frequencies of renal anomalies (50%) and intracranial hemorrhage (12%) were significant. The high incidence of chronic otitis media (35%) has not been reported previously. One patient had a renal transplant. Vascular compromise as a pathologic mechanism for some characteristics of the syndrome is also suggested by the presence of small bowel stenosis and atresia, tracheal and bronchial stenosis, renal artery stenosis, middle aortic syndrome, and avascular necrosis of the humeral and femoral heads. Twenty (47%) patients underwent liver transplantation. Five of six who underwent Kasai procedure required liver transplantation. Twelve died (28%), five after liver transplantation. One patient died of intracranial bleeding. Sixteen (37%) without liver transplantation and 15 (35%) who underwent liver transplantation are alive.

CONCLUSIONS: Some patients with early-onset and more severe liver disease can benefit from liver transplantation. Careful and complete assessment should be made of infants with a cholestatic syndrome, to avoid misdiagnosis and unnecessary Kasai procedures. Our observation of vascular compromise in various organ systems suggests that notch signaling pathway defects affect angiogenesis in Alagille syndrome.

 

TREATMENT CHARACTERIZATION
GENERAL  
TRANSPLANTATION  
Orthotopic liver transplantation for alagille syndrome.

Maldini G, Torri E, Lucianetti A, Guizzetti M, Pinelli D, Bertani A, Corno V, Giovanelli M, Zambelli M, Stroppa P, Alberti D, Torre G, Spada M, Gridelli B, Colledan M.

Ospedali Riuniti di Bergamo, Bergamo, Italy.
Transplant Proc. 2005 Mar;37(2):1174-6. Abstract quote  

Alagille syndrome (AS) is a dominantly inherited, multisystem disorder involving the liver, heart, eyes, face, and skeleton. From October 1997 through July 2004, 260 pediatric orthotopic liver transplantations (OLTx) were performed in 231 patients. This report describes 21 patients of median age 1.95 years (range, 0.7-16.7) who had alagille syndrome.

We present the technical features of the OLTx, incidence and type of complications, medical conditions related to the syndrome, need for retransplantation, as well as patient and graft survival rates. A split liver technique was used in 16 patients (76%) who received a left lateral segment (LLS) graft whereas 7 patients (33%) received a whole liver. Only cadaveric donors were used. The major surgical complications requiring reintervention in 11 patients (52%) included biliary problems (19%) and vascular complications (17%). One case of hepatic artery thrombosis required retransplantation. Three recipients (14%) died. All other patients are alive with an actuarial survival rate of 90% at 1 year and 80% at 5 years.

The actuarial graft survival rate is 85% at 1 year and 75% at 5 years. Patients with AS, despite the associated cardiovascular anomalies, can be treated successfully by a combined approach between cardiologist, radiologist, cardiothoracic, and liver transplant surgeons.

With careful planning and operative management, the results are comparable with those obtained with other more common cholestatic diseases.
Living-related liver transplantation for Alagille syndrome.

Kasahara M, Kiuchi T, Inomata Y, Uryuhara K, Sakamoto S, Ito T, Fujimoto Y, Ogura Y, Oike F, Tanaka K.

Organ Transplant Unit, Department of Transplant Surgery, Kyoto University Hospital, Kyoto, Japan.
Transplantation. 2003 Jun 27;75(12):2147-50. Abstract quote  

Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by chronic cholestasis, congenital heart disease, peculiar facies, butterfly-like vertebrae, and posterior embryotoxon.

Liver dysfunction is the common presentation of AGS, and liver transplantation may be indicated. This study examines the outcome of living-related liver transplantation (LRLT) for AGS. Twenty patients with AGS (median age 5.0 years, range 0.6-12.9) underwent LRLT at Kyoto University Hospital between June 1990 and February 2002. Five potential donors were excluded because of paucity of intrahepatic bile ducts diagnosed by preoperative liver biopsy and one because of a hepatic vascular anomaly.

The overall 5-year patient survival was 80.4%. Three patients died as the result of the following: complications related to surgery, heart failure caused by progressive pulmonary artery stenosis, and a graft with unsuspected bile duct paucity.

Liver dysfunction was improved in all successful cases, and catch-up growth occurred in 90% of patients. LRLT is an efficacious treatment modality for AGS if donors are selected by cautious evaluation to rule out unsuspected bile duct paucity.

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Last Updated June 7, 2005

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