CASE REPORT

Diagnostic and management difficulties in Alagille syndrome – case report

 Dificultăţi de diagnostic şi tratament în sindromul Alagille – prezentare de caz

First published: 03 iunie 2024

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Pedi.73.1.2024.9653

Abstract

Alagille syndrome (ALGS) is a multisystem autosomal do­mi­nant disorder caused by variants in one of the JAG1 or the NOTCH2 genes. It presents with a wide spectrum of clinical manifestations that most commonly include he­pa­tic, cardiac, skeletal, ophthalmologic and renal ab­nor­ma­li­ties, along with characteristic facial features. The prog­no­sis and mortality risk vary according to the different or­gan involvement and its severity, and the management re­quires a multidisciplinary approach, depending on the find­ings of each affected individual. We report the case of a 2-year-old boy who presented with neonatal cholestasis, dis­tinc­tive facial features and pulmonary artery stenosis, who progressively developed severe hypercholesterolemia, hy­per­tri­gly­ce­ri­de­mia and intractable pruritus, with a sig­ni­ficant decrease in the quality of life. 

Keywords
Alagille syndrome, neonatal cholestasis, pruritus, quality of life

Rezumat

Sindromul Alagille este o afecţiune autozomal-dominantă mul­ti­sis­te­mi­că, determinată de variante ale uneia dintre genele JAG1 sau NOTCH2. Acest sindrom prezintă un spectru larg de manifestări clinice, care includ cel mai frecvent ano­­ma­lii he­pa­ti­ce, cardiace, scheletice, oftalmologice şi renale, ală­turi de trăsături faciale caracteristice. Prog­nos­ti­cul şi riscul de mor­ta­li­ta­te variază în funcţie de im­pli­ca­rea diferitelor or­ga­ne­ şi de severitatea aces­teia, iar managementul pa­cienţilor necesită o abordare mul­ti­dis­ci­pli­na­ră, în funcţie de par­ti­cu­­­la­­­r­i­tăţile fie­că­rui individ. Pre­zen­tăm cazul unui băiat în vârstă de 2 ani, care a asociat co­les­ta­ză neonatală, trăsături fa­­cia­­le distinctive şi stenoză de arteră pulmonară, dezvoltând pro­­gre­­siv hiper­co­les­te­ro­le­mie şi hipertrigliceridemie severe, alături de prurit re­fra­ctar, cu scăderea semnificativă a calităţii vieţii. 

Introduction

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder caused by a variant in one of the JAG1 or the NOTCH2 genes, with an incidence of 1 in 70,000 live births(1). It presents with a wide spectrum of clinical manifestations that most commonly include hepatic (paucity of intrahepatic bile ducts on liver biopsy, cholestasis), cardiac (congenital cardiac defects primarily involving the pulmonary arteries), skeletal (butterfly vertebrae), ophthalmologic and renal abnormalities, along with characteristic facial features. ALGS has a various presentation across different age groups and even among individuals from the same family, ranging from subclinical manifestations to severe and life-threatening hepatic and cardiac disease(1,2). Cholestasis is one of the main causes of morbidity in patients with ALGS, alongside underlying cardiac and renal disorders(1). It can cause severe pruritus that becomes intractable with time, hypercholesterolemia and cirrhosis that can lead to end-stage liver disease in up to 15% of the cases(3,4). Therefore, these infants need to be periodically monitored by a multidisciplinary team for possible complications.

Case report

We report the case of a 2-year-old boy who was referred to our service at 7 days of age with neonatal cholestasis. Thirty hours after birth, the patient presented with respiratory distress, lethargy and feeding difficulties. The laboratory tests revealed significant inflammatory syndrome, direct hyperbilirubinemia, and elevated asphyxia markers. The case was interpreted as early-onset neonatal sepsis, and the patient received empiric antibiotic therapy with ampicillin and gentamicin, with good outcomes. However, the jaundice intensified, associating hyperchromic urine with progressively increasing levels of gamma-glutamyl transferase and direct hyperbilirubinemia; thereby, he was transferred to our clinic for further investigations. The family history revealed that the patient’s mother had schizophrenia and took olanzapine during pregnancy, his father had been operated on for a congenital heart defect during childhood, and also had a particular phenotype that could be suggestive of Alagille syndrome, and his older brother died of complex cardiac anomaly. On clinical exam, he had dysmorphic facial features (triangular face, hypertelorism, low-set ears), jaundice, mild axial hypotonia, and grade II systolic murmur, with no he­pato­splenomegaly. The laboratory findings showed slightly elevated serum transaminases (aspartate- aminotransferase [ASAT] 87 U/L, alanine-aminotransferase [ALAT] 56 U/L), cholestasis (gamma-glutamyl transpeptidase [GGT] 923 U/L), direct hyperbilirubinemia (total bilirubin 15.63 mg/dl, direct bilirubin 8.41 mg/dL), and high triglycerides (324 mg/dL). Abdominal ultrasound revealed liver and spleen with normal appearance, therefore excluding biliary atresia, while the echocardiogram found pulmonary artery stenosis. We also excluded various infections associated with hepatitis (Epstein-Barr virus, cytomegalovirus, toxoplasmosis, syphilis) and hypothyroidism. We initiated treatment with ursodeoxycholic acid, and we continued to monitor and evaluate the patient through periodic checkups.

Over the following admissions, serum transamina­ses and GGT maintained increasingly high levels, and the echocardiographic findings were consistent with the persistence of pulmonary artery stenosis. At the same time, the patient’s facial features became more and more suggestive of Alagille syndrome (Figure 1).

Figure 1. Characteristic facial features of Alagille syndrome in our patient
Figure 1. Characteristic facial features of Alagille syndrome in our patient


The ophthalmologic evaluation revealed posterior embryotoxon. We confirmed the diagnosis with genetic testing that found a heterozygous pathogenic variant of the JAGGED1 gene (c.703C>T, p.Arg235*). We started the treatment with rifampicin, loratadine, vitamin D, vitamin K and B-vitamins complex, and a hypercaloric diet with a special formula for infants with chronic liver disease (Heparon junior®) and maltodextrin supplement (Polycal®). The evolution was progressive, with growth failure, hepatosplenomegaly, xanthomatosis (Figure 2), severe pruritus, malabsorption syndrome, vitamin D deficiency, and severe hyperlipidemia (cholesterol 1179 mg/dL, triglycerides 327 mg/dL). For the treatment of hyperlipidemia, we initiated atorvastatin, which was well tolerated, and managed to lower cholesterol and triglyceride levels slowly. The pruritus became intractable over time, interfering with the child’s ability to sleep during the night and, thus, severely affecting the quality of life. Therefore, the treatment with maralixibat chloride, an ileal bile acid transporter inhibitor used to treat pruritus in children with ALGS, was started, with quick and significant clinical improvement.

Figure 2. Xanthomatosis in our patient as a complication of high serum levels of cholesterol in Alagille syndrome
Figure 2. Xanthomatosis in our patient as a complication of high serum levels of cholesterol in Alagille syndrome

Discussion

Alagille syndrome is an autosomal dominant disorder with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to a variant in the JAG1 gene (20p12, ALGS type 1; 90%), and more rarely due to neurogenic locus notch homolog protein (NOTCH2 gene, 1p13) mutation (ALGS type 2), 5-7%(5). The NOTCH2 gene codes for the notch protein, while JAG1 codes for cell surface protein Jagged1, a ligand for notch receptors. The signals originating from these receptors are involved in organogenesis(1). Jagged1 is found in periportal mesenchyme, biliary cells, portal endothelium and hepatic arteries, and activates a Notch2 cascade in the ductal plate. Notch2 is required for bile duct formation and, in its absence, ducts fail to develop, and disorganized biliary structures are formed(6). The expression pattern of Jagged1 and Notch2 in the endothelium, the cardiac neural crest cells and the smooth muscle cells of the pulmonary arteries are linked to the cardiac defects in Alagille syndrome(7). The variants in ALGS are inherited in approximately 30-50% of cases, while de novo mutations cause the remaining 50%(1).

Alagille syndrome is usually first suspected in children based on their clinical features. One of the first symptoms of ALGS is jaundice, presenting as early as two weeks of life. The characteristic dysmorphic facial features become more obvious as the infants grow, and include a high forehead with frontal bossing or flattening, deep-set eyes with moderate hypertelorism, a pointed chin, and a saddle or straight nose with a bulbous tip. These features give the face the appearance of an inverted triangle(8,9).

Structural cardiac disease – predominantly right-sided anomalies – is a cause of high morbidity and mortality in patients with Alagille syndrome. The most commonly reported lesions include branch pulmonary artery stenosis or hypoplasia (76%), tetralogy of Fallot (12%) and left-sided lesions, such as valvular and supravalvular aortic stenosis (7%). Tetralogy of Fallot in ALGS tends to be more severe, and it is more likely associated with pulmonary atresia in comparison with the general population(10). The majority of cardiovascular issues are hemodynamically insignificant; however, it has been found that the more severe malformations have accounted for most of the early mortality in patients with ALGS(8). The highest mortality rate was reported at 75% in patients with tetralogy of Fallot and pulmonary atresia(10).

The liver is the most commonly involved organ in Alagille syndrome, with paucity of bile ducts being present in 75-100%. Intrahepatic bile duct paucity is associated with cholestasis (conjugated hyperbilirubinemia with high GGT, increased serum bile acids, and elevated cholesterol and triglycerides) that manifests with jaundice, pruritus, and potentially disfiguring or disabling xanthomas. Complications of this unremitting cholestasis include fat malabsorption, which leads to failure to thrive and fat-soluble vitamin deficiency(9-11). Vitamin K deficiency is the cause of coagulopathy in AGLS patients, rather than liver dysfunction, while low levels of vitamin D are associated with increased bone fracture risk(10,12). The most debilitating symptom of cholestasis in ALGS is intense pruritus, which is amongst the worst of any cholestatic liver disease. It is seen in most children by the third year of life, and it often disturbs sleep, daily activities, and cognitive development(13). Progressive liver damage can lead to cirrhosis and end-stage liver disease, and it may ultimately require liver transplantation(11).

Skeletal abnormalities in Alagille syndrome include a wide variety of vertebral anomalies. The most common is the butterfly vertebrae, which is a sagittal defect in the vertebral body caused by failure of fusion of the two lateral chondrification centers during embryogenesis. Patients are asymptomatic, and there is no structural significance to the finding, but it can aid in diagnosis(14,15).

The most common ocular finding in individuals with ALGS is posterior embryotoxon, diagnosed by a slit-lamp examination. Posterior embryotoxon is the prominence of the centrally positioned Schwalbe’s ring (or line) at the point where the corneal endothelium and the uveal trabecular meshwork join. It has been reported in 78-89% of individuals with ALGS. Posterior embryotoxon does not affect visual acuity and has an incidence of 8-15% in the general population(9,16).

Other clinical manifestations of Alagille syndrome include renal abnormalities. Structural problems such as small, echogenic kidneys, cysts, renal dysplasia, and ureteropelvic obstruction, as well as functional abnormalities, particularly renal tubular acidosis, all occur in ALGS(10,16).

In patients with a suspected diagnosis of Alagille syndrome, the evaluation should include liver function tests, serum cholesterol and triglycerides, bile acids, complete blood cell count, coagulation studies, liver and renal ultrasound, cardiology evaluation, ophthalmic evaluation, spine radiography, and genetic testing, to confirm the diagnosis(14). The high variability of clinical manifestations in ALGS can also be a cause of diagnosis difficulty. In our case, we first considered the mother’s olanzapine intake during pregnancy as a possible cause for the patient’s cholestasis. Then, based on the father’s suggestive phenotype (characteristic facies and history of congenital heart disease), we suspected the Alagille syndrome. During the following checkups, the facial features became more distinctive, and the laboratory tests showed progressive evolution of the cholestasis, therefore validating a higher probability of ALGS. No correlation has been found between the different pathogenic variants in JAG1 and NOTCH2 probands and the variable expressivity of Alagille syndrome. The same variant can be associated with a wide range of clinical findings, even within families. Therefore, it is not possible to predict the severity and the disease burden, due to the absence of genotype-phenotype correlations(10). This was also the case in our patient’s family. Based on the child’s positive genetic diagnosis, as well as the history of congenital heart disease, we suspect that the father also suffers from ALGS. Still, because of the lack of long-term complications, he remained undiagnosed. His brother also died of an unknown complex cardiac malformation, which could have also been part of an ALGS diagnosis. As a result, we recommended genetic testing within the family as well.

Alagille syndrome prognosis and mortality risk vary with the different organ involvement and its severity, and the management needs a multidisciplinary approach, depending on the findings of each affected individual. Regarding liver disease, the treatment is mainly supportive, trying to alleviate severe pruritus and xanthomas with choleretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone). Surgical partial internal biliary diversion and ileal exclusion have also been used for this purpose without preventing the progression of liver disease(4,9). Indications for liver transplantation in patients with ALGS are represented by refractory pruritus, decompensated cirrhosis, recurrent upper gastrointestinal bleeding, and hepatopulmonary syndrome(17). The improvement of the liver parameters and some catch-up in growth have been reported in almost 90% of cases after liver transplantation. Still, the prognosis usually depends on associated cardiac and renal impairment(5). Correction of vitamin deficiencies with appropriate vitamin dosage and the use of hypercaloric nutrition are also important for optimal growth and development in patients with Alagille syndrome(3,10). The large variety of variants of the JAG1 and NOTCH2 genes pose a unique challenge for developing targeted treatments. Recently, ileal bile acid transporter inhibitors maralixibat and odevixibat have been approved for the treatment of pruritus in children aged 1 year and older with ALGS, with trials showing a significant decrease in the severity of pruritus(3,18). The inhibition of the ileal bile acid transporter results in the decreased reabsorption of bile acids (primarily the salt forms) from the terminal ileum and increased excretion of bile acids in the feces. This results in the lowering of systemic levels of bile acids, potentially reducing bile acid-mediated liver damage and the related complications(19). Our patient also benefited from maralixibat treatment, with a considerable improvement in the quality of life after the first month of treatment.

Regarding the presence of xanthomas and persistent hyperlipidemia in our patient, we associated atorvastatin. Atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, was used with good results in children with hypercholesterolemia, but few reports were published in infants. Also, atorvastatin may upregulate hepatic CYP7A1 mRNA through small heterodimer partner SHP downregulation at the transcriptional level, reducing the cholesterol level by conversion to bile acids(20). After a few months of treatment, the serum cholesterol and triglyceride levels decreased, but still, they were maintained at high levels. As a result, liver transplantation is taken into consideration if the disease continues to progress.

Conclusions

Alagille syndrome is a complex disease with a wide variety of clinical manifestations that range from minimal and hardly recognizable symptoms to debilitating and life-threatening complications. Genetic and prenatal counseling is difficult because of the lack of genotype-phenotype correlations. The same mutation can cause different grades of severity and organ involvement. These patients need to be closely monitored by a multidisciplinary team that includes specialists in hepatology, cardiology, nutrition, nephrology and ophthalmology.   

 

Corresponding author: Alina Grama E-mail: gramaalina16@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.

Bibliografie

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