Diagnosis: Alagille Syndrome
The combination of persistent jaundice, triangular face, and butterfly vertebrae is diagnostic of Alagille syndrome, an autosomal dominant multisystem disorder caused by mutations in JAG1 (95%) or NOTCH2 (5%) genes. 1, 2
Clinical Presentation
The triad presented in this infant represents three of the five classic diagnostic features of Alagille syndrome:
- Persistent jaundice reflects intrahepatic bile duct paucity causing cholestasis, which is the most common presenting symptom in 89-93.8% of cases 3, 4, 5
- Triangular facies (also described as characteristic facial features including triangular face, hypertelorism, and prominent chin) is present in 100% of fully expressed cases 1, 4
- Butterfly vertebrae represent the skeletal manifestation, occurring in 43.8-47% of patients 1, 4, 5
Immediate Diagnostic Workup Required
Cardiac evaluation is mandatory before any surgical intervention, as 50% of patients have cardiac defects (most commonly peripheral pulmonary stenosis) that significantly complicate management and liver transplantation. 2
The diagnostic algorithm should proceed as follows:
- Obtain JAG1 and NOTCH2 genetic testing to confirm diagnosis before considering any surgical intervention 2
- Perform echocardiography to identify cardiac malformations present in 75-95% of cases 4, 5
- Ophthalmologic examination for posterior embryotoxon (present in 67% of cases) 4
- Measure serum GGT, total cholesterol, ALT, AST, and total bile acid levels, which are significantly elevated in Alagille syndrome compared to biliary atresia 5
Critical Differential Diagnosis
Biliary atresia must be excluded urgently, as neonatal biopsies may appear obstructive in both conditions, making histology unreliable for early differentiation. 2 However, key distinguishing features favor Alagille syndrome:
- Hypercholesterolemia is characteristic of Alagille syndrome (predominantly lipoprotein X elevation) and significantly higher than in biliary atresia 1, 5
- Presence of dysmorphic facial features and butterfly vertebrae are not seen in biliary atresia 6, 7
- Elevated GGT, TBA, and ALT levels are significantly higher in Alagille syndrome versus biliary atresia 5
Common Diagnostic Pitfalls
Not all classic features of Alagille syndrome are present at initial diagnosis, and the condition shows highly variable expressivity even within the same family. 2, 6 The frequency of new mutations is relatively high (15-50%), so absence of family history does not exclude the diagnosis 6.
Do not proceed with Kasai portoenterostomy without first ruling out Alagille syndrome through genetic testing and cardiac evaluation, as this surgical intervention is inappropriate for Alagille syndrome and cardiac defects must be identified pre-operatively 8, 2.
Prognosis and Management Implications
Only 50% of Alagille syndrome patients survive to adulthood without liver transplantation, making early genetic diagnosis and monitoring essential 2. The presence of vascular anomalies (cerebral aneurysms, internal carotid narrowing, abdominal coarctation, renal artery stenosis) adds complexity to transplant decisions and requires pre-transplant evaluation 1.
Complex heart anomalies and progressive liver dysfunction result in significant morbidity and mortality, with deaths occurring from both cardiac and hepatic failure 4.