> Alagille Syndrome | Alpha-1 Antitrypsin Deficiency | Bile Acid Synthesis Defects | Mitochondrial Hepatopathies | PFIC (Progressive Familial Intrahepatic Cholestasis)

*Please Note: The images used below are large, please allow time for download.

Alagille Syndrome

Definition

Alagille syndrome is a dominantly inherited systemic disorder consisting of abnormalities of the liver, heart, eye, spine, facies, kidney, vasculature and other organs. It is caused by mutations in Jagged1, a ligand in the Notch signaling pathway. A minority of patients in whom a Jagged1 mutation could not be identified have recently been found to have mutations in Notch2, a receptor in the Notch signaling pathway. Notch genes control cell fate determination, and are active during (and sometimes after) fetal development. Mutations in Notch ligands and receptors have recently been demonstrated to cause several disorders of embryogenesis.

Dr. Daniel Alagille, a French Pediatric Gastroenterologist, first described a syndrome consisting of a characteristic facies, intrahepatic bile duct paucity and cholestasis, heart murmur, butterfly vertebrae and posterior embryotoxon in 1969. Since that original description, abnormalities in other organs have been recognized to be common manifestations in Alagille syndrome. Originally, the disorder was termed Syndromic Bile Duct Paucity and Arteriohepatic dysplasia, but more recently it has been reclassified as Alagille syndrome, in part because patients may not necessarily have bile duct paucity or even clinical liver disease.

Etiology

AGS is one cause of neonatal cholestasis, with an incidence of approximately 1:70,000 live births. It is inherited in autosomal dominant fashion, but approximately 60% of cases are caused by de novo mutations. AGS is a genetically heterogenous disorder, caused by mutations in the Notch signaling pathway ligand gene, Jagged1, or the gene for its receptor, Notch2. At this time the vast majority of patients have mutations in Jagged1 (94%) with only a small subset (<1%) having mutations in Notch2. Notch signaling is triggered when a ligand on the surface of one cell communicates with a Notch receptor of the surface of an adjacent cell. The end result of Notch signaling affects cell fate determination. Notch was first discovered in Drosophila, where mutations cause a characteristic notching in the wing. Notch and its ligands (Jagged, Delta and Serrate) are apparently active embryologically in all of the organs affected in Alagille syndrome. Mutations in members of the Notch signaling pathway have been shown to cause human disease. Mutations in Notch1 have been found to cause aortic valve abnormalities, mutations in Notch3 cause CADASIL (cerebral autosomal dominant arteriopathy and stroke), and mutations in the Notch ligand delta-like3 (dll3) cause the autosomal recessive disorder spondylocostal dysostosis.

The location of the causative gene was first suggested by case reports of AGS associated with cytogenetically visible deletions of the long arm of chromosome 20. Deletions overall account for approximately 7% of AGS, and can easily be detected by FISH. In 1997, mutations in Jagged1 were shown to be the cause of AGS. Mutations are now demonstrated in approximately 90% of patients with clinical AGS. The majority of the mutations detected result in protein truncation, and haploinsufficiency is the presumed mechanism of pathogenesis. The mutations are distributed widely over the entire coding region, and most are unique. The gene is quite large, and as a result mutation testing is laborious. There is no apparent genotype-phenotype relationship, even for patients with total gene deletion. There is extreme variability of phenotype, even within families, suggesting that other modifying genes or environmental factors contribute significantly to the manifestations of the disease.

Genetic evaluation for Jagged1 mutations is currently available both on a research and a commercial basis. Molecular screening for Notch2 is a research test only, at this time. Prenatal testing for Jagged1 mutations is available and accurate if the mutation has previously been identified in the proband. Preimplantation genetic diagnosis has been successfully performed. The molecular testing has aided in the diagnosis of AGS for patients with only minor or atypical manifestations. It has expanded the phenotype to include a pedigree with only cardiac manifestations and one with deafness as a major feature. Finally, a study of relatives of probands has shown that the majority of patients with Jagged1 mutations have less severe disease or only minor manifestations that would not meet the classical diagnostic criteria of Alagille, but which obviously might result in progeny with severe or fatal manifestations of the syndrome. Further testing for mutations of Jagged1 in other related disorders is likely to further expand the phenotypes associated with this gene and the Notch signaling pathway.

Clinical Features

Hepatic features:Intrahepatic intralobular bile duct paucity is one of the most common features of AGS, however it may not be present in many infants younger than 6 months of age, and may not be present in many mildly affected individuals. Bile duct paucity is defined as a ratio of bile ducts to portal tracts of less than 0.5 in a liver biopsy with an adequate (≥10) number of portal tracts present (Figure 1). The normal number of bile ducts in a portal tract increases throughout the first years of life, reaching a normal ratio of nearly 2 by adolescence. The normal ratio in premature infants is less than 1, so care must be taken in this group when interpreting liver histology.

Many infants present with cholestatic jaundice in the first days or months of life. Typically, the total and conjugated bilirubin and GGT are quite elevated. Discrimination from biliary atresia is very important, but can be difficult, particularly from the polysplenia type of biliary atresia. In biliary atresia, the DISIDA scan will not show excretion into the intestines, however half of AGS patients will also demonstrate no excretion in this age group. In general, a percutaneous liver biopsy can discriminate biliary atresia (with bile duct proliferation) from AGS (with bile duct paucity), but in younger infants there is considerable overlap of the histologic pattern. In biliary atresia, an operative cholangiogram will not demonstrate continuity of the ducts from the intrahepatic to distal extrahepatic tree. Unfortunately, the intrahepatic tree in AGS can be extremely hypoplastic, and apparent (but incorrect) non-opacification of the proximal ducts has resulted in a significant number of AGS patients being misdiagnosed as biliary atresia, and therefore receiving a Kasai hepatoportoenterostomy. It is unclear whether this operation adversely changes the course of AGS, but it certainly is of no benefit.

The severity of cholestasis in AGS patients is highly variable. Nevertheless, patients with AGS may have very significant cholestasis compared to other pediatric liver disease. Typically the cholestasis worsens throughout the first months or years of life, and then in many patients there is a subsequent gradual improvement. Peak values can include total bilirubin > 20 mg/dl, GGT > 2,000 U/L, cholesterol > 2,000 mg/dl and bile acid levels >100 times normal. Hepatic synthetic function is usually well maintained. In infants and children, xanthomas are common, and can be quite extensive. Pruritus can be debilitating, despite therapy with ursodeoxycholic acid, hydroxyzine, rifampin and bile salt binding agents. Patients with severe cholestasis may respond to partial external biliary diversion, shunting a portion of the bile flow from the gallbladder into a cutaneous ostomy

Hepatomegaly is more common than splenomegaly. Portal hypertension develops in up to 1/3 of patients with severe hepatic AGS. It is difficult to estimate the percentage of patients that progress to end-stage liver disease, but of infants who are severely affected this number is probably 20-30%. When all patients with Jagged1 mutations are considered, this number is substantially lower. Generally, if portal hypertension is absent at 5 years of age and cholestasis is mild, eventual liver failure is extremely unlikely.

Cardiopulmonary features: : Alagille recognized that a murmur was the most common single feature of the syndrome. The majority of these murmurs are caused by peripheral pulmonary artery stenosis (PPS) (Figure 2) rather than an intracardiac or valvular process. The PPS can be severe, and can cause highly disparate perfusion of the right versus left lung. Most patients, however, have trivial PPS. About 7-11% of AGS patients have significant structural cardiac disease, usually arising in the right heart embryologically. The most important lesion is tetralogy of Fallot, which is sometimes accompanied by pulmonary atresia. Large series of AGS cardiac lesions have been described. Correction of these lesions can be complicated by the significant pulmonary artery stenoses that increase resistance to right heart flow. The presence and type of intracardiac lesions are major factors in infancy that predict excess mortality in AGS.

Ocular abnormalities:A large number of ocular manifestations may occur in AGS. Posterior embryotoxon is the most important diagnostically. Posterior embryotoxon is a prominent, centrally positioned Schwalbe’s line (Figure 3). It generally does not affect vision. It occurs in many (56-95% of different series) AGS patients, but has also been reported to occur in 8-15% of normal eyes. Axenfeld anomaly (iris strands) is seen in 13% of AGS patients. Optic disk drusen has been seen in a majority of patients with AGS.

Facial abnormalities:The typical facies in childhood consist of a prominent forehead, deep set eyes with moderate hypertelorism, a small pointed chin, and a saddle or straight nose. This has been termed triangular facies (Figure 4). Other abnormalities have been noted, including large ears. The typical facies in adults with AGS do not resemble the childhood features. The forehead becomes less prominent, and the chin is more protuberant.

Skeletal abnormalities:The characteristic manifestation of AGS is the sagittal cleft or butterfly vertebrae, which is found in 33-87% of patients (Figure 5). Due to a failure of the fusion of the anterior arches of the vertebrae, the vertebral body is split sagittally into paired hemivertebrae. This anomaly may occur in other syndromes and also in healthy individuals. It is generally not of structural significance.

Severe metabolic bone disease with pathologic fracturing is common in AGS. Factors that may contribute to osteopenia include chronic malnutrition, deficiencies of vitamins D and K, chronic hepatic and renal disease, mineral deficiency and pancreatic insufficiency.

Central Nervous System abnormalities: Stroke, intracranial bleeding and CNS vascular anomalies occur in patients with AGS, and have contributed significantly to morbidity and mortality. Intracranial bleeding has occurred in up to 15% of cases presenting with liver disease in some series, and is fatal in approximately one third of events. The majority of this bleeding has occurred in the absence of a significant coagulopathy. Head trauma, generally of a minor nature, has been associated with a number of bleeding events. Structural vascular lesions, including aneurysms and moyamoya, have been identified in some patients with AGS (Figure 6).

Renal abnormalities:It is now recognized that renal abnormalities are an important feature of AGS. Major structural disease can occur, including cystic and dysplastic kidneys, solitary kidney, and duplicated ureters (Figure 7). Renal artery stenosis is a cause of systemic hypertension. Tubular disease, including renal tubular acidosis, tubulointerstitial nephropathy, and glomerular lipidosis has been seen in AGS. In adults, there may be progression to renal failure, and some infants with AGS present with neonatal renal failure. AGS caused by Notch2 mutations appears to be associated with a predominantly renal phenotype.

Diagnosis:

The diagnosis of Alagille syndrome was traditionally made only with the combination of bile duct paucity in association with at least three of five major criteria: cholestasis, heart murmur, embryotoxon, butterfly vertebrae and facies. These diagnostic criteria substantially underestimated the number of patients ultimately shown to have Jagged1 mutations, and overestimated the incidence of major criteria. Subsequent studies have shown that many patients have mild or subclinical manifestations, and that Jagged1 mutations have highly variable expressivity. The identification of Jagged1 mutations and the availability of molecular testing have greatly improved the understanding about and diagnosis of AGS. It has confirmed the clinical impression that nearly all minimally affected relatives who manifest one or two minor features of AGS will carry the gene mutation. Since the transmission risk for their progeny is high, it seems appropriate to designate these mutation positive individuals as AGS. Therefore, revised criteria for clinical and molecular diagnosis has been proposed (Table 1). Some mutation positive individuals will have only one or even no clinical features, yet may have severely affected progeny.

Table 1: Revised Diagnostic Criteria for the Diagnosis of Alagille syndrome

Major clinical criteria include consistent 1) cardiac, 2) ocular disease, 3) butterfly vertebrae, 4) characteristic "Alagille" facies or 5) renal disease.

*A number of index cases with 2 or even 1 criterion will ultimately be shown to have AGS by molecular testing, but 2 criteria should be considered insufficient to establish the diagnosis in a proband.

Treatment

Treatment of AGS is based on improving bile flow using ursodeoxycholic acid (UDCA:15-25 mg/kg/day, maintaining optimal nutrition, preventing fat-soluble vitamin deficiencies, addressing pruritus and hypercholesterolemia, and treatment of any extrahepatic features. For relief of severe pruritus unresponsive to antihistamines, UDCA, rifampin and bile acid-binding resins, partial biliary diversion has been successful in many patients.

Liver transplantation is effective therapy for some patients with hepatic AGS. Indications for liver transplantation include synthetic liver failure, intractable portal hypertension, uncontrollable pruritus, severe bone disease (hepatic osteodystrophy) and growth failure related to malabsorption or liver failure. Following transplantation, jaundice, xanthomas and pruritus resolve. Bone density may significantly improve post-transplant, however, growth failure may not. Living related donor selection must be done with caution, as 40% of parents will carry the Jagged1 mutation, and, even if asymptomatic, may have severely hypoplastic bile ducts that make segmental live-donor donation impossible. Patients with AGS may have significant renal disease, cardiac disease and malnutrition, each of which may contribute to increased morbidity or mortality of transplantation. Multiple organ transplantation has been successfully performed occasionally in AGS.

Prognosis

Most series of AGS report data from severely affected individuals who present with neonatal cholestasis. In these studies, there is approximately 50-75% survival without liver transplantation by 20 years of age. The decreased survival is due predominantly to cardiac, hepatic and central nervous system disease. Rarely, patients develop hepatocellular carcinoma. Family members who are identified because of disease in the proband generally have milder manifestations that have no significant impact on longevity.

Alagille Syndrome References: Top 25 to 2005 (09/15/2005) Chronologic order

Alagille D, et al.: Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases, J Pediatr 110:195-200, 1987.

Sokol RJ, Stall C: Anthropometric evaluation of children with chronic liver disease, Am J Clin Nutr 52:203-208, 1990.

Bucuvalas JC, et al.: Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature, J Clin Endocrinol Metab 76:1477-1482, 1993.

Hoffenberg EJ, et al.: Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy, J Pediatr 127:220-224, 1995.

Heubi JE, Higgins JV, Argao EA, Sierra RI , Specker BL: The role of magnesium in the pathogenesis of bone disease in childhood cholestatic liver disease: a preliminary report, Jour Pediatr Gastroent Nutr 25:301-6, 1997.

Li L, et al.: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1, Nat Genet 16:243-251, 1997.

Oda T, et al.: Mutations in the human Jagged1 gene are responsible for Alagille syndrome, Nat Genet 16:235-242, 1997.

Krantz ID, et al.: Spectrum and frequency of Jagged1 (JAG1) mutations in Alagille syndrome patients and their families, Am J Hum Genet 62:1361-1369, 1998.

Krantz ID, et al.: Jagged1 mutations in patients ascertained with isolated congenital heart defects, Am J Med Genet 84:56-60, 1999.

Emerick KM, et al.: Features of Alagille syndrome in 92 patients: frequency and relation to prognosis, Hepatology 29(3):822-829, 1999.

Crosnier C, et al.: Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome, Gastroenterology 116:1141-1148, 1999.

Quiros-Tejeira RE, et al.: Variable morbidity in Alagille syndrome: a review of 43 cases, Jour Pediatr Gastroent Nutr 29(4):431-7, 1999.

Woolfenden AR , et al.: Moyamoya syndrome in children with Alagille syndrome: additional evidence of a vasculo­pathy, Pediatrics 103:505-508, 1999.

Loomes KM, et al.: The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome, Hum Mol Genet 8:2443-2449, 1999.

Crosnier C, Lykavieris P, Meunier-Rotival M, Hadchouel M: Alagille syndrome. The widening spectrum of ateriohepatic dysplasia, Clinics Liver Disease 4(4):765-78, 2000.

Crosnier C, et al.: JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome, Hepatology 32(3):574-81, 2000.

Jones EA, Clement-Jones M, Wilson DI: JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype, Journal Medical Genetics 37(9):663-8, 2000.

Lykavieris P, Hadchouel M, Chardot C, Bernard O: Outcome of liver disease in children with Alagille syndrome: a study of 163 patients, Gut 49(3):431-5, 2001.

Eldadah ZA, et al.: Familial Tetralogy of Fallot caused by mutation in the Jagged1 gene, Human Molecular Genetics 10(2):163-9, 2001.

Piccoli DA, Spinner NB: Alagille syndrome and the Jagged1 gene , Semin Liver Dis 21(4):525-34, 2001.

McElhinny DB, Krantz ID, Bason L, Piccoli DA, Emerick KM, Spinner NB, Goldmuntz E: Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome, Circulation 106(20):2567-74, 2002.

Emerick KM, Whitington PF: Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome, Hepatology 35(6):1501-6, 2002.

Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB: Consequences of JAG1 mutations. Journal of Medical Genetics 40(12):891-5, 2003.

Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M: Bleeding tendency in children with Alagille syndrome, Pediatrics 111(1):167-70, 2003.

Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 109(11):1354-8, 2004.

McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet. 2006 Jul;79(1):169-73.

Updated: 19 December 2006

Home | Glossary | Frequently Asked Questions | Contact Web Master | Accessibility | Disclaimer | Site Map

Return to RDCRN Main Page