ALAGILLE-WATSON SYNDROME
ARTERIOHEPATIC DYSPLASIA
CHOLESTASIS WITH PERIPHERAL PULMONARY STENOSIS
HEPATIC DUCTULAR HYPOPLASIA, SYNDROMATIC
ALAGILLE SYNDROME
ALGS1
ALGS
AWS
AHD
Syndromic bile duct paucity due to monosomy 20p12
Arteriohepatic dysplasia due to monosomy 20p12
Alagille syndrome due to monosomy 20p12
Alagille syndrome due to del(20)(p12)
Alagille-Watson syndrome due to monosomy 20p12
Alagille syndrome is an autosomal dominant disorder that traditionally has been defined by a paucity of intrahepatic bile ducts, in association with 5 main clinical abnormalities: cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype ... Alagille syndrome is an autosomal dominant disorder that traditionally has been defined by a paucity of intrahepatic bile ducts, in association with 5 main clinical abnormalities: cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype (Li et al., 1997). Cholestasis is a direct consequence of the paucity of bile ducts. About 39% of patients also have renal involvement, mainly renal dysplasia (Kamath et al., 2012). Turnpenny and Ellard (2012) reviewed the clinical features, diagnosis, pathogenesis, and genetics of Alagille syndrome. - Genetic Heterogeneity of Alagille Syndrome Another form of Alagille syndrome (ALGS2; 610205) is caused by mutation in the NOTCH2 gene (600275).
Diagnosis in a proband is made if bile duct paucity is accompanied by 3 of the main 5 clinical criteria (Alagille et al., 1987). It has been suggested that family members should be considered affected if they express ... Diagnosis in a proband is made if bile duct paucity is accompanied by 3 of the main 5 clinical criteria (Alagille et al., 1987). It has been suggested that family members should be considered affected if they express any of the 5 main clinical features (variable expressivity) (Watson and Miller, 1973; Dhorne-Pollet et al., 1994). Gonioscopy with demonstration of embryotoxon is a valuable way to make the diagnosis in mildly affected persons (Romanchuk et al., 1981). In a review of the Alagille syndrome, Turnpenny and Ellard (2012) noted that the diagnosis can be difficult in some patients who do not show unequivocal classic features of the disorder.
In addition to neonatal jaundice, features of this syndrome include the following: in the eye, posterior embryotoxon and retinal pigmentary changes; in the heart, pulmonic valvular stenosis as well as peripheral arterial stenosis; in the bones, abnormal vertebrae ... In addition to neonatal jaundice, features of this syndrome include the following: in the eye, posterior embryotoxon and retinal pigmentary changes; in the heart, pulmonic valvular stenosis as well as peripheral arterial stenosis; in the bones, abnormal vertebrae ('butterfly' vertebrae) and decrease in interpediculate distance in the lumbar spine; in the nervous system, absent deep tendon reflexes and poor school performance; in the facies, broad forehead, pointed mandible and bulbous tip of the nose and in the fingers, varying degrees of foreshortening (Watson and Miller, 1973; Alagille et al., 1975; Rosenfield et al., 1980). Histology of the liver demonstrates few intrahepatic bile ducts. Shulman et al. (1984) described a kindred with 5 affected persons in 3 generations. Severity varied widely. In 2 sisters, neonatal jaundice, peripheral pulmonic stenosis, and characteristic facies including broad forehead, deep-set eyes, prominent nose, and pointed chin were features. One died at age 5 years of cirrhosis with portal hypertension and the other at 18 months of congestive heart failure. Their asymptomatic mother and maternal aunt had similar facial appearance, pulmonic stenosis, skeletal anomalies, and bilateral posterior embryotoxon. The maternal grandfather, who refused evaluation, had a similar appearance, history of liver disease, and a heart murmur. Li et al. (1997) pictured clinical features of Alagille syndrome, including prominent forehead, pointed chin, posterior embryotoxon, and butterfly vertebra due to abnormal clefting of the vertebral bodies. Liver biopsy demonstrated multiple branches of the hepatic artery and portal vein in the portal tract without any accompanying bile ducts. Based on 56 of their own observations, Krantz et al. (1997) showed that all affected persons have hepatic, cardiac, and facial abnormalities. Vertebral defects were found in 59%, renal in 23%, and ocular in 83% of examined patients. Two persons in their group had pancreatic insufficiency. Lykavieris et al. (2001) reviewed the clinical outcome of 163 French patients with Alagille syndrome presenting in childhood. All patients had at least 3 of the 5 major clinical features. Overall, the prognosis was found to be worse in children presenting with neonatal cholestatic jaundice, although severe complications were possible even after late-onset liver disease. The authors argued for close lifelong follow-up. - Liver Involvement In the 3 cases studied by Berman et al. (1981), cholestasis was not progressive and, although the SGPT was chronically elevated (122-520 units per liter), features of liver cell failure did not develop. Riely et al. (1979) gave a useful differential diagnosis of familial intrahepatic cholestasis: Zellweger syndrome (see 214100), cholestasis-lymphedema syndrome (214900), Byler disease (211600), and cholestasis with defective formation of cholic acid (214950). Alpha-1-antitrypsin deficiency (613490) may present as neonatal cholestasis with a paucity of intrahepatic bile ducts. In a longitudinal study, Dahms et al. (1982) sought to account for the pathologic hallmark of arteriohepatic dysplasia, namely, the paucity or absence of intrahepatic bile ducts. Liver biopsies under 6 months of age showed intrahepatic cholestasis and portal inflammation and in 2 of 5 cases giant cell transformation. None showed congenital absence of interlobular bile ducts; 3 of 5 had normal numbers of interlobular bile ducts, and 2 of 5 had paucity. Three of 5 showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later (ages 3 to 20 years) showed the characteristic paucity or absence. By this time cholestasis and inflammation had largely resolved but some fibrosis persisted. An acquired bile duct deficiency, possibly due to destructive inflammation of duct epithelium, was suggested. This disorder should be considered in all infants with cholestasis. The histologic diagnosis may be difficult or impossible in infancy. The diagnosis in that age group must rest on the syndromatic features. Hepatocellular carcinoma has been reported in children with Alagille syndrome (Ong et al., 1986; Kaufman et al., 1987; Rabinovitz et al., 1989) and in an adult with Alagille syndrome without cirrhosis (Adams, 1986). Legius et al. (1990) speculated that loss of heterozygosity for a cell cycle-regulating gene rather than underlying chronic liver disease may be the explanation of liver carcinoma. - Craniofacial Involvement Sokol et al. (1983) proposed that the facies seen in ALGS is nonspecific and secondary to congenital intrahepatic cholestasis from many causes. Mueller et al. (1984) reviewed phenotypic features of 56 reported cases of Alagille syndrome and 7 of their own. They emphasized a characteristic facies with prominent forehead and chin with deep-set eyes and eye changes, usually asymptomatic: anterior chamber anomalies, which may be associated with eccentric or ectopic pupils, and retinal changes of chorioretinal atrophy and pigment clumping. Also see review by Mueller (1987). Krantz et al. (1997) pictured the supposedly characteristic facies of 5 patients, including a mother and daughter and a father and daughter. Posterior embryotoxon in a father and daughter with ALGS was also pictured. Kamath et al. (2002) reported 2 patients with mutation-proven ALGS who also had unilateral coronal craniosynostosis. They found no mutations in genes known to be associated with craniosynostosis and suggested that the JAG1 gene plays a role in cranial suture formation. Kamath et al. (2003) studied 53 JAG1 mutation-positive relatives of 34 ALGS probands and found the characteristic facies to be the most highly penetrant feature. Kamath et al. (2002) reported that the 49 clinical dysmorphologists they asked to examine a photographic panel of 18 pediatric and adult individuals with ALGS and other forms of congenital intrahepatic cholestasis correctly identified the ALGS facies 79% of the time, suggesting that the facies is specific to ALGS. Sokol (2004) and Kamath et al. (2004) exchanged letters regarding the evidence for and against a distinct facies in Alagille syndrome. - Skeletal Involvement Rosenfield et al. (1980) described abnormalities in the shape and segmentation of vertebral bodies and short distal phalanges. - Ocular Involvement Raymond et al. (1989) described Axenfeld anomaly in a 24-year-old black man with other signs of Alagille syndrome: congenital intrahepatic biliary atresia, systolic ejection murmur, short stature, butterfly vertebra at T-10, and hand changes (short ulnae, short scaphoids, and short distal phalanges). From a study of 22 children with Alagille syndrome and 23 of their parents, Hingorani et al. (1999) concluded that Alagille syndrome is associated with a characteristic group of ocular findings without apparent serious functional significance and probably unrelated to fat-soluble vitamin deficiency. Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of Alagille syndrome, eliminating the need for extensive and invasive investigations. The most common ocular abnormalities in patients were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%, a previously unreported finding), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Microcornea was not associated with large refractive errors, and visual acuity was not significantly affected by these ocular changes. Ocular abnormalities, including posterior embryotoxon, iris abnormalities, and optic disc or fundus pigmentary changes, were detected in 1 parent in 36% of cases. - Kidney Involvement LaBrecque et al. (1982) described 15 affected persons in 4 generations. They demonstrated renal dysplasia, renal artery stenosis, and hypertension in some. Martin et al. (1996) described 3 children with Alagille syndrome, in 2 of whom a unilateral multicystic dysplastic kidney was detected by prenatal ultrasound; in the other, a solitary cortical cyst was found later in childhood. All had normal renal function, growth, and liver synthetic function but continued to have clinical and biochemical signs of cholestasis. Thus the authors concluded that Alagille syndrome should be included in the differential diagnosis of cystic kidney disorders associated with cholestatic liver disease. In a retrospective study involving 187 patients with Alagille syndrome due to JAG1 mutations who had evaluable renal information, Kamath et al. (2012) found that 73 (39%) had a renal anomaly or disease. Most (58.9%) had renal dysplasia, followed by renal tubular acidosis (9.5%), vesicoureteral reflux (8.2%), urinary obstruction (8.2%), and chronic renal failure (5.4%). Renal dysplasia was defined by increased echogenicity of the kidneys, reflecting increased fibrous tissue. Many of the patients had impaired glomerular filtration rates (GFR). There were no genotype/phenotype correlations. Kamath et al. (2012) cited evidence indicating that the Notch signaling pathway is involved in kidney development, and suggested that renal involvement may be considered a disease-defining feature of Alagille syndrome. - Cardiovascular Involvement Mueller et al. (1981) studied 7 patients in 5 families and reviewed 62 reported cases. Of the 69 cases, death from cardiovascular or hepatic complications occurred by age 5 years in 16. Woolfenden et al. (1999) described 2 children with sporadic Alagille syndrome associated with moyamoya (252350). They interpreted this finding as indicating that Alagille syndrome is a vasculopathy. Raas-Rothschild et al. (2002) found descriptions of abdominal coarctation of the aorta in 3 reported cases of ALGS. They described a fourth case in which, in addition to abdominal coarctation, there was right subclavian stenosis. Lykavieris et al. (2003) reviewed the records of 174 patients with Alagille syndrome without liver failure and found that 22% had spontaneous or postprocedure bleeding in various organs. The authors suggested that patients with ALGS are at special risk for bleeding. Although they could not exclude a role for hypercholesterolemia, they speculated that abnormalities in the JAGGED1 signaling pathway may impair hemostatic function. In a retrospective chart review of 268 individuals with ALGS, Kamath et al. (2004) found that 25 (9%) had noncardiac vascular anomalies or events, and that vascular accidents accounted for 34% of mortality in this cohort. The documented vascular anomalies included basilar and middle cerebral artery aneurysms, internal carotid artery anomalies, aortic aneurysms, and coarctation of the aorta; 1 patient had moyamoya disease. Kamath et al. (2004) concluded that vascular anomalies are a major cause of morbidity and mortality in patients with ALGS. - Other Features In a 36-day-old male with typical features of Alagille syndrome, Rodriguez et al. (1991) found associated caudal dysplasia sequence: imperforate anus, rectourethral fistula, lumbosacral abnormalities, and dysplastic right kidney. Bucuvalas et al. (1993) concluded that growth-retarded children with Alagille syndrome are insensitive to growth hormone (GH; 139250). They thought that the growth disturbance and metabolic defects may be due in part to failure to increase IGF1 (147440) concentrations in response to GH, implying that such patients may benefit from IGF1 treatment. In a 19-year-old woman with Alagille syndrome diagnosed at the age of 8 years, Kato et al. (1994) described papillary thyroid carcinoma (see 188550) with multiple lung metastases. They reviewed 12 reported cases of hepatocellular carcinoma. Development of carcinoma was as early as age 2 years and as late as 48 years. Ho et al. (2000) described a 3-year-old Asian boy with Alagille syndrome who had severe generalized xanthomas, including oral xanthomas, and marked hypodontia. Kamath et al. (2002) reported the presence of supernumerary digital flexion creases, a finding reported in less than 1% of the general population, in 16 of 46 (35%) ALGS probands examined.
Oda et al. (1997) and Li et al. (1997) demonstrated that Alagille syndrome is caused by mutations in the human homolog of Jagged-1 (JAG1; 601920), which encodes a ligand for NOTCH1 (190198). Oda et al. (1997) generated a ... Oda et al. (1997) and Li et al. (1997) demonstrated that Alagille syndrome is caused by mutations in the human homolog of Jagged-1 (JAG1; 601920), which encodes a ligand for NOTCH1 (190198). Oda et al. (1997) generated a cloned contig of the critical region revealed by cytogenetic deletions and used fluorescence in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region they identified JAG1, the human homolog of rat Jagged-1, which encodes a ligand for the NOTCH1 receptor. Cell-cell Jagged/Notch interactions are critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon/intron structure of JAG1 allowed them to perform detailed mutational analysis of DNA samples from non-deletion ALGS patients, revealing 3 frameshift mutations, 2 splice donor site mutations, and 1 mutation abolishing RNA expression from the altered allele. They concluded that ALGS is caused by haploinsufficiency of JAG1. Li et al. (1997) mapped the human JAG1 gene to the Alagille syndrome critical region within 20p12, and demonstrated 4 distinct coding mutations in JAG1 in 4 Alagille syndrome families. Yuan et al. (1998) analyzed the JAG1 gene in 8 Alagille syndrome families. Four categories of mutations were identified: (1) 4 frameshift mutations in exons 9, 22, 24, and 26 were exhibited respectively in affected individuals in 4 ALGS families, which resulted in moving the translational frame of JAG1; (2) 1 nonsense mutation, a 1-bp substitution in exon 5 of the EGF-like repeat domain, was detected in 2 unrelated ALGS families, which altered codon 235 from arginine to stop; (3) 1 acceptor splice site mutation in exon 5 was found in a sporadic patient; and (4) a 1.3-Mb deletion, which included the entire JAG1 gene, was found in another patient. All of the mutations were present in heterozygous form, supporting the dominant inheritance of Alagille syndrome. Giannakudis et al. (2001) detected parental mosaicism for a JAG1 mutation in 4 of 51 families where mutations had been identified in the ALGS patients and where parental DNA was available. In each of the 4 families, the parent with mosaicism exhibited only the characteristic face with or without an embryotoxon posterior but no other features of ALGS. One case was observed where mosaicism was present in the patient himself, reflecting a somatic mosaicism due to a deletion of the JAG1 gene. Giannakudis et al. (2001) suggested that the high prevalence of parental mosaicism be taken into account in diagnosis, genetic counseling, and prognosis in ALGS. They also suggested that the high failure rate in mutation detection in ALGS patients may in part be due to mosaicism. In a patient with abdominal aortic coarctation with right subclavian stenosis, Raas-Rothschild et al. (2002) identified a deletion mutation in the JAG1 gene (601920.0013). Kamath et al. (2002) reported monozygotic twins with Alagille syndrome who were concordant for a mutation in JAG1 (601920.0014) but discordant for a clinical phenotype. One twin had severe pulmonary atresia with mild liver involvement, whereas the other had tetralogy of Fallot and severe hepatic involvement that required a liver transplant. El-Rassy et al. (2008) screened an ALGS proband and his JAG1 mutation-positive father and sister for additional mutations in the NOTCH2 and HEY2 (604674) genes but found no additional mutations. The proband had severe liver failure, mild pulmonary stenosis, and dysmorphic facial features. His 7-year-old sister had the same dysmorphic facial features, mild developmental delay, and elevated liver function enzymes, and his father had only mild dysmorphic facial features and mild retinitis pigmentosa. El-Rassy et al. (2008) suggested that other genes in the JAG/NOTCH pathway might be implicated in the diverse phenotypes seen in this family. Among 230 patients with tetralogy of Fallot, Rauch et al. (2010) found that 3 (1.3%) had Alagille syndrome associated with JAG1 mutations.
Danks et al. (1977) gave an estimated minimum population frequency of 1 in 70,000 births, when ascertained by the presence of neonatal jaundice. Li et al. (1997) considered the true incidence most likely higher.