Ocular abnormalities in Alagille syndrome

Alagille syndrome (AGS) is a rare genetic disorder inherited in autosomal dominant pattern that affects the liver, heart, and other organ systems. Major feature of AGS is liver damage caused...

Alagille syndrome is an autosomal dominant condition with incomplete penetrance that is associated mostly with hepatic, cardiac, and skeletal abnormalities. In addition, the association of Alagille syndrome with ocular abnormalities is well known and is considered one of the characteristic features of this condition. Most commonly, posterior embryotoxon, glaucoma, or retinopathy has been identified in these children. The authors present 2 patients with Alagille syndrome who, before the age of 3 years old, developed idiopathic intracranial hypertension with documented increased intracranial pressure by lumbar puncture and papilledema, which was responsive to acetazolamide.

The current study aimed to analyze through a literature review evidence of association between ocular changes and non-syndromic cleft lip and/or palate (NSCL/P). A literature review was carried out in accordance with the Cochrane Collaboration Group protocol. PubMed, Scopus, Academic Google and ISI Web of Science databases were systematically searched. A total of 16 studies were accessed, and three made up the final sample.All three studied ocular abnormalities in patients with NSCL/P.The articles found ocular abnormalities in 6.21%, 17.54% and 1.03% of patients respectively.The presence of ocular abnormalities in patients with NSCL/P was significant in this systematic review, but the articles all agreed that future studies should explore the possibility of a greater occurrence of ocular changes in individuals with NSCL/P.

Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease.

BackgroundAlagille syndrome, a rare genetic disorder with autosomal dominant transmission, manifests with five major features: paucity of interlobular bile ducts, characteristic facies, posterior embryotoxon, vertebral defects, and peripheral pulmonary stenosis. Globally, only 500 cases have so far been reported, with only five cases reported in the Indian subcontinent. Rarely, Alagille syndrome also presents with skin manifestations and early-onset chronic liver disease, which was found in our case. We believe that we report what could be the first case of Alagille syndrome presenting with café au lait spots, as no such published case report could be found in the literature.Case presentationWe report an unusual case of childhood cholestatic jaundice with neonatal onset of jaundice. A 10-year-old boy from the Indian subcontinent presented with obstructive jaundice from early infancy. He also had recurrent fractures of his upper limb bones, intermittent bleeding from his nose, productive cough, decreased night vision, hyperpigmented spots over his skin, and progressive enlargement of his abdomen. Histological examination of a liver biopsy specimen revealed a paucity of bile ducts and changes suggestive of chronic liver disease. Our patient was diagnosed with Alagille syndrome and managed conservatively but died 1 year after the final diagnosis.ConclusionsThis particular syndromic form of paucity of bile duct disorder has been rarely reported in the Indian literature so far. Our case is notable because the child had café au lait spots and very early onset of chronic liver disease, which is quite rare in Alagille syndrome. We believe this to be the first case report on Alagille syndrome manifesting with café au lait syndrome and such early onset of chronic liver disease.

We report on a patient with a de-novo deletion of chromosome 6p. This male infant presented with multiple systemic congenital defects together with an unusual ocular phenotype. Slit-lamp examination revealed thin, opaque, rectilinear bands within the anterior segment partially connecting iris to corneal endothelium. These were associated with bilateral hyperopia and optic nerve hypoplasia. Ocular abnormalities in such patients have been documented although the number of individuals is small and identical cytogenetic defects are rarely encountered. We compare the clinical findings in this case with previously described phenotypes. Characterisation of such cases is important as it is becoming apparent that deletion of genetic information encoded on chromosome 6p has implications for ocular embryogenesis.

The Association of Alagille Syndrome and Craniosynostosis

Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia. Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA. The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998). We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

We report a rare case of a 10 year old girl diagnosed as having Alagille syndrome on the basis of a characteristic face, posterior embryotoxon, cholestasis, peripheral pulmonary artery stenosis and the absence of interlobular bile ducts in a liver biopsy at 1.5 years of age. Since 1.5 years old, she had been in good health without medication and the serum biochemical liver function tests indicated no progression of cholestasis. A second liver biopsy at 9.5 years of age showed normal interlobular bile ducts confirmed by anti-keratin staining at each of the five examined portal areas. Alagille syndrome is usually associated with the progressive disappearance of interlobular bile ducts. The findings of interlobular bile ducts in the second liver biopsy were therefore rare and unique to this case.

Ocular findings in patients with cholestatic disorders of infancy: A single-centre experience

Introduction: The aim of this report is to describe a case of gastrointestinal bleeding that started at 1 month of age in a patient with Alagille Syndrome. Case report: Patient started recurrent gastrointestinal bleeding, leading to hypovolemic shock in the second month of life. During the investigation, cholestasis and incoagulable INR were evidenced. The facial stigmata, associated with the posterior embryotoxon in the ophthalmologic examination and transthoracic echocardiogram with stenosis of the pulmonary branches and patent foramen ovale, suggested the hypothesis of Alagille Syndrome, later confirmed by compatible liver biopsy and genetic testing with a mutation in the JAGGED1 gene. After administration of vitamin K, the patient evolved with normalization of the coagulogram, without new episodes of gastrointestinal bleeding. At follow-up, replacement of fat-soluble vitamins and treatment with ursodeoxycholic acid were initiated. Discussion: Reports in the literature describe bleeding episodes in patients with Alagille Syndrome, however, the main site of bleeding is the central nervous system. There is no description of bleeding in the gastrointestinal tract as the initial and neonatal manifestation of the syndrome. The case reported is an uncommon form of presentation and shows the importance of diagnostic suspicion in cases of neonatal cholestasis with gastrointestinal bleeding, allowing for adequate treatment and improved prognosis.

Purpose:The aims of this study were to evaluate the clinical manifestations and prognosis of the syndromic and nonsyndromic intrahepatic bile duct paucity (IHBDP).Methods: We studied histology of 42 infants with neonatal cholestasis.Fourteen patients were diagnosed as IHBDP.We evaluated the clinical manifestations, courses and prognosis retrospectively.Results: Underlying disease of the 42 infants with neonatal cholestasis were biliary atresia in 23, intrahepatic bile duct paucity in 14 (Alagille syndrome in 4 and nonsyndromic IHBDP in 10), neonatal hepatitis in 5 infants.The mean ratio of the bile ducts per portal tract was 0.087 (range: 00.5).The manifestations in 4 patients with Alagille syndrome demonstrated as follows: characteristic face in 3, chronic cholestasis in 4, posterior embryotoxon in 2, vertebral anomalies in 2, peripheral pulmonary stenosis in 2. One of 4 patients of Alagille syndrome improved cholestasis and the other 3 patients were remained their cholestasis and growth retardation.All patients of the nonsyndromic IHBDP were idiopathic.Seven out of 8 patients of nonsyndromic IHBDP showed improvement of cholestasis, and one patient received liver transplantation due to cirrhosis. Conclusion:This study suggested that IHBDP should be considered in the differential diagnosis of neonatal cholestasis.The outcome of idiopathic IHBDP was better than predicted.

Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome.

Alagille syndrome (AS) is a multisystemic disease autosomal dominant, with variable expression. The major clinical manifestations are: chronic cholestasis, congenital heart disease, posterior embryotoxon in the eye, characteristic facial phenotype, and butterfy vertebrae. AS is caused by mutations in JAGGED1 (more than 90%) and in NOTCH2. Differential diagnosis include: infections, genetic-metabolic diseases, biliary atresia, idiopathic cholestasis. Cholestasis, pruritus and xanthomas have been successfully treated with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). In certain cases, partial external biliary diversion has also proved successful. Liver transplantation is indicated in children with cirrhosis and liver failure.

Alagille syndrome (ALGS) is a rare autosomal dominant genetic disorder with multisystem involvement including the liver, heart, skeleton, eyes, kidneys, and other organ systems, along with characteristic facial abnormalities. Some patients with ALGS may have isolated involvement of a particular system, such as a heart defect like the tetralogy of Fallot, an atrial septal defect (ASD), a characteristic facial appearance, or an isolated vertebral body anomaly. These individuals may or may not have liver anomalies or other features typically seen in the disorder. We report the case of a four-year-old female child with moderate ostium secundum ASD and branch pulmonary artery stenosis diagnosed since three months of age who presented with classical features of facial dysmorphism, posterior embryotoxon in the right eye, butterfly presentation of the T5 vertebra, delayed mental development, and history of recurrent infections. Bilateral branch pulmonary artery plasty with glutaraldehyde-treated pericardial patch and direct closure of the ASD leaving a patent foramen ovale was performed to correct the cardiac malformations. The surgery was uneventful without any postoperative complications. Currently, as no curative management of the disorder is available, the syndromic medical and surgical approach remains the mainstay in managing this condition.