Genetics & clinical manifestations: Alas is inherited in an autosomal dominant pattern, with mutation in JAG1 gene that is responsible for Alas in > 9
Alagille syndrome (Alas)
Genetics & clinical manifestations: Alas is inherited in an autosomal dominant pattern, with mutation in JAG1 gene that is responsible for Alas in > 90 % of ptns; a small % may show mutations in NOTCH2 gene. It’s characterized by the paucity of interlobular bile ducts with associated criteria include:
1) Hepatic manifestations:
1. Chronic cholestasis 87-100 %.
2. Jaundice 66-85 %.
3. Cirrhosis 44-95 %
4. Pruritus 59-88 %
5. Xanthomas 30-42 %
2) Cardiac murmur/anomalies 63-98 %: Most common: peripheral PS (pulmonic stenosis); Fallot tetralogy, ductus arteriosus, septal defects, or aortic coarctation .
3) Butterfly vertebrae 24-87 %.
4) Ocular: most common: posterior embryotoxon (prominent Schwalbe line 56- 95 %)
5) Dysmorphic facies: broad nasal bridge, triangular facies, + deeply set eyes 78-95 %.
6) Renal affection 19-74 %: Most common: renal dysplasia; glomerular mesangio-lipidosis or renal tubular acidosis
Short stature and/or failure to thrive are commonly observed in Alas. Delayed developmental is observed in some of ptns and could be partly due to malnutrition. Supernumerary digital flexion creases hv bn observed in 35 % of Alas ptns, compared to <1 % of normal subjects. Malformed Cerebral & systemic vasculature may be also present, including intracranial alterations predisposing to stroke. Moreover, conjugated hyperbilirubinemia, and increased serum aminotransferases, & gamma-glutamyl transpeptidase (GGTP).
Dgx: Clinical Dgx of Alas in infants with cholestasis include clinical features + liver biopsy showing decreased number of the interlobular bile ducts. Marked paucity of bile ducts may not be evident in young infants < 6 mo. These infants may show proliferative bile duct, like obstructive cholestasis. Ptns with clinical characteristics of Alas, Dgx can be established by documenting JAG1 or NOTCH2 genetic mutation. Subjects identified by genetic testing (e.g., relatives of Alas) may have mild features. More data available in: Genetic Registry website. DD: paucity of interlobular bile ducts in Alas may be seen in other disorders, e.g., a-1 antitrypsin (AAT) deficiency, cystic fibrosis (CF), infectious episodes (e.g., CMV, syphilis), mitochondrial disorder, progressive familial intrahepatic cholestasis (PFIC1 & PFIC2), or arthrogryposis-renal dysfunction-cholestasis syndrome.
Management: Therapeutic keys may be as follows:
(1) Cholestatic liver disease is of variable severity and may be stable by school age & management is conservative, with ttt for pruritus & malabsorption as equired. Portoenterostomy (Kasai procedure) of no benefits & not advised.
(2) Pruritus is commonly seen with cholestasis, observed in 80 % of ptns, and may adversely impact quality of life. Pruritus can be ttt with ursodeoxycholic acid (ursodiol), rifampin, or bile acid sequestrants (e.g., cholestyramine, colesevelam). Colesevelam is available & more palatable compared to cholestyramine. Moreover, naltrexone therapy can improve pruritus in children having cholestatic disease,
(3) Malnutrition + stunted growth & delayed pubertal are commonly seen and could be ttt with high-energy supplements (needs nasogastric or gastrostomy feeding) + fat-soluble vitamins. Pancreatic insufficiency is uncommon in Alas, so pancreatic enzymes is unlikely used as an additional therapy for malnutrition.
(4) Magnitude of cardiac or renal disease & its management is highly variable.
(5) Considering vascular abnormalities that can augment the risk of intracranial bleeding, there should be a lowered threshold for an urgent brain imaging.
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