A 9-year-old Chinese boy with Alagille syndrome

Alagille syndrome (AGS, OMIM#118450) is a multi-system, autosomal dominant disorder with variable clinical manifestation, which primarily affects the liver, heart, eyes, face, and skeleton. The estimated incidence of AGS is 1 in 70 000 births of all races worldwide;^1-3 however it has been rarely reported in Chinese children. We treated a Chinese boy presenting with jaundice, pruritus and growth failure finally who had been diagnosed as having AGS. Informed consent was obtained from the legal guardian of the child before reporting.

CASE REPORT

The Chinese boy aged 9 years and 7 months, with a history of jaundice since infancy, was the only child of his non-consanguineous parents and born at term after an uncomplicated pregnancy. There was no significant family history and his parents were healthy. Icterus had been present since two months of age, with light yellow stools, progressive pruritus and failure to thrive. At 2 years of age, his height was 73.5 cm (＜3 centile) and head circumference was 45 cm (＜3 centile).

Physical examination showed that he was mildly jaundiced and stunted with a height of 125 cm (<10 centile for 9 years of age) and a weight of 22.5 kg (<10 centile for 9 years of age). He had facial dysplasia showing a broad forehead, deep-set eyes and a straight nose (Fig. 1). A grade Ⅱ/Ⅵ systolic murmur was heard over the second left intercostal space. The rest of systemic examination was normal.

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Fig. 1. Facial characteristics of a Chinese boy with Alagille syndrome (A and B).

Laboratory test revealed the levels of serum transaminases, γ-glutamyl transpeptidase (GGT), alkaline phosphatase (AKP), bilirubin and cholesterol were elevated (alanine aminotransferase 353 IU/L (normal value: 5–50); aspartate aminotransferase 340 IU/L (normal value: 5–55); GGT 403 IU/L (normal value: 5–50); AKP 390 IU/L (normal value: 15–350); total bilirubin 34.7 µmmol/L (normal value: 1.0–24.0); direct bilirubin 24.7 µmmol/L (normal value: 0–8.0); and cholesterol 7.17 mmol/L (normal value: 2.0–5.67)). HBsAg, anti-HCV antibody, anti-HIV antibody, and TORCH screening were negative. Serum ceruloplasmin was normal. Chest X-ray showed nothing abnormal and abdominal ultrasound showed mild echogenicity of the liver. Echocardiography revealed a secondary atrial septal defect (diameter 1.1 cm). Liver biopsy showed hepatocellular swelling with partial vacuolar degeneration, portal inflammation and paucity of interlobular bile ducts (Figs. 2 and 3).

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Fig. 2. HE staining of liver specimens showing paucity of the interlobular ducts (Original magnification ×100).
Fig. 3. Cytokeratin stainings of liver specimens confirming the absence of bile ducts in the portal tract (Original magnification ×100).

DISCUSSION

Alagille syndrome is an autosomal dominant disorder with 5 major features: chronic cholestasis, cardiovascular malformations (most often peripheral pulmonary stenosis), posterior embryotoxon, vertebral defects (typically butterfly vertebrae) and characteristic facies (broad forehead, deep-set eyes, straight nose and pointed chin). Less common clinical features include renal abnormalities, growth and mental retardation, intracranial bleeding, and pancreatic insufficiency.^1-3 AGS is caused by mutations of the Jagged1 gene, which encodes a ligand in the Notch signaling pathway. This pathway functions in many cell types throughout the development to regulate cell fate decisions.⁴

The diagnosis of AGS has been diagnosed based on the presence of intrahepatic bile duct paucity on liver biopsy (defined histologically as a ratio of interlobular bile ducts to portal tracts that is less than 0.5) in association with three or more major features.^1,2 The clinical definition has been broadened to two of these major features if the individual has a positive family history, and to one of these major features if the patient has a Jagged1 defect.³

The phenotype presentation in AGS varies in severity and clinical significance even within the same families. Some of the affected children may present with life-threatening congenital heart disease or hepatic failure, whereas others may be only subclinical cases.² Bile duct paucity has been considered the most important and constant feature of AGS. The pathogenesis of this paucity is currently not well understood, but it is likely that mutations in Jagged1 leads to a lack of branching and elongation of bile ducts during postnatal liver growth.⁵ Most patients' symptoms present in the first year of life. Hepatic manifestations vary typically from mild to severe cholestasis. Audible heart murmurs as the most common manifestation of AGS are mostly caused by stenosis at some level of the pulmonary tree or in structural intracardiac disease.^2,3

Our case had 3 of the five major features (chronic cholestasis, congenital heart disease and peculiar facies) associated with paucity of interlobular bile duct in liver biopsy (interlobular bile ducts were invisible in 10 portal areas). The presence of these features is consistent with the diagnosis of AGS. In addition to the three major features,the present case showed severe growth retardation since infancy. Growth failure, a common manifestation of AGS, has been reported in 50% to 90% of patients with AGS. Growth failure in AGS is not completely understood, but it may be attributable to insufficient caloric intake,steatorrhea from the liver and/or pancreatic disease, and primary defect in the Jagged1 gene.^6,7

The long-term prognosis of AGS varies and is related to the severity of hepatic or cardiac involvement. Nearly all early deaths in AGS are ascribed to cardiac disease, whereas most late deaths are due to hepatic complications and intracranial bleeding. Liver transplantation is eventually necessary in 21% to 31% of the patients with AGS. Indications for the transplantation include either chronic liver failure,intractable portal hypertension or impaired life quality with growth failure, extensive xanthomatosis, and refractory pruritus.^3,8,9 A study of AGS demonstrated the estimated 20-year survival rate of 75% for 92 patients with AGS, 80% for those not requiring hepatic transplantation, and 60% for those undergoing transplantation.²

REFERENCES

1. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001; 21: 525-534. [PubMed]

2. Emerick KM, Rand EB, Goldmuntz E, Krantz ID , Spinner NB , Piccoli DA. Features of Alagille syndrome in 92 Patients: Frequency and Relation to Prognosis. Hepatology 1999; 29: 822-829. [PubMed]

3. Piccoli DA. Alagille syndrome. In: Suchy FJ, Sokol RJ, et al. Liver disease in children. 2nd ed. Philadelphia: Lippincott Williams &Wilkins; 2001: 327-342.

4. Crosnier C, Attie-Bitach T, Encha-Razavi F, Audollent S, Soudy F, Hadchouel M, et al. Jagged 1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology 2000; 32: 574-581. [PubMed]

5. Libbrecht L, Spinner NB, Moore EC, Cassiman D, Van Damme-Lombaert R, Roskams T. 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. Am J Surg Pathol. 2005; 29: 820-826.[PubMed]

6. Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, et al. Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr 2002; 35: 495-502.[PubMed]

7. Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Gornbein JA, et al. Does liver transplantation affect growth pattern in Alagille syndrome? Liver Transpl 2000; 6: 582-587.[PubMed]

8. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001; 49: 431-435.[PubMed]

9. Englert C, Grabhorn E, Burdelski M, Ganschow R. Liver transplantation in children with Alagille syndrome: Indications and outcome. Pediatr Transplant 2006; 10: 154-158.[PubMed]