Congenital genetic diseases sometimes display characteristic clinical manifestations that direct physicians to conduct the necessary tests to arrive at a correct diagnosis. However, other genetic diseases may be more insidious and are diagnosed only later in life (if at all), which means the early window for the initiation of critical medical intervention is missed. 

When it comes to rare diseases, physicians can sometimes miss the signs and symptoms presented right under their noses. This is because modern medical decision-making often works as a yes/no algorithm; most physicians adopt a “wait-and-see” approach to illnesses that do not fit in any clear category. Physicians then take further steps when the disease has progressed past a certain threshold. 

In a sense, this is necessary, since the investigation of every possible symptom with the worst possible diagnosis in mind is simply not feasible. The mantra for young doctors is that “common things are common”—which is true, unless they are not. 

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Alagille syndrome is a multiorgan disease that was first described by scientists in 1979 who discovered a group of patients who demonstrated extrahepatic clinical features. Scientists reported a curious mix of pathologies, including chronic cholestasis, characteristic facial features, posterior embryotoxon, vertebral arch defect, and structural heart disease. 

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At that time, without the advanced molecular diagnostics that we have today, a diagnosis of Alagille syndrome was made when 3 out of the 5 features were observed, together with bile duct paucity. The disease was discovered to be inherited in an autosomal dominant manner. 

Early Detection of Symptoms 

It remains crucial that Alagille syndrome is diagnosed as early as possible, and this is a highly achievable goal in developed nations. What aids the diagnosis of Alagille syndrome is the group of 5 characteristic symptoms mentioned earlier, which should lead physicians to conduct further investigations. 

One of the most prominent features of Alagille syndrome is liver disease. Chronic cholestasis in the early stages of the disease is known to resolve in a proportion of patients with Alagille syndrome, thus throwing into doubt the usefulness of liver transplantation, which is a high-risk procedure. Studies have also shown that markers of cholestasis, such as total bilirubin and cholesterol, often peak in infancy and normalize in the period that follows. 

However, the liver manifestations of Alagille syndrome go even further. Many patients develop portal hypertension by age 20, complicated by asictes, gastrointestinal bleeding, and splenomegaly. 

“These data suggest that in [Alagille syndrome], cholestasis peaks in the first years of life but portal hypertension commonly develops later, with associated complications, and often requires liver transplantation during childhood,” Gilbert and Loomes wrote in Translational Gastroenterology and Hepatology. 

In infants, cholestatic liver disease can sometimes lead to growth failure, which can be severe enough that a liver transplantation is warranted. The good news is that liver transplantation, when indicated, can usually improve growth-related parameters quickly and effectively post-operation. 

Ocular and Cardiac Ramifications 

We would be amiss not to discuss the other features of Alagille syndrome, particularly the ones that are visible to the naked eye. Patients with Alagille syndrome tend to have characteristic features such as a high prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip. 

Granted, these facial features may not be readily distinguishable in infants. However, it should be noted that the overwhelming number of people with Alagille syndrome demonstrate these characteristics, which highlights the importance of a thorough examination of the facial features of a patient when Alagille syndrome is suspected. 

“Numerous ocular abnormalities have been reported in [Alagille syndrome], of which posterior embryotoxon is the most common feature reported in 56–95% of patients,” Ayoub and Kamath wrote in Diagnostics. “It is prominence of the lines of Schwalbe and is detected by slit lamp examination in the anterior chamber of the eye.”

However, it is important to note that these findings are not pathognomonic for Alagille syndrome, as they are found in around 22% of the general population. Another ocular feature of Alagille syndrome that is more specific to this disease is optic disk drusen. Studies demonstrate that about 95% of patients display these symptoms in one eye while 80% display them in both eyes. 

Besides the liver manifestations of Alagille syndrome, cardiac abnormalities are most commonly reported in patients with this disease. Studies demonstrate that about 94% of patients had cardiac involvement, with predominance on the right side. Among the most commonly reported cardiac manifestations of Alagille syndrome are tetralogy of Fallot (12%), branch pulmonary artery stenosis or hypoplasia (76%), and valvular and supravalvular aortic stenosis (7%). 

Read more about Alagille syndrome diagnosis 

“Complex cardiac disease is responsible for early death in 15% of patients with [Alagille syndrome] and is associated with a predicted 6-year survival of only 40%,” Ayoub and Kamath wrote. 

In addition, skeletal involvement may be present in Alagille syndrome, which can be inconsequential or result in significant deformity. The most commonly reported sign is butterfly vertebrae, observed in around 35% of individuals. In addition, patients with Alagille syndrome have a higher risk of suffering from a bone fracture. 

Given the manifold manifestations of Alagille syndrome, a thorough physical examination and subsequent investigations should be sufficient to alert physicians to the possibility of this diagnosis. As this disease remains exceedingly rare, it is imperative that physicians are trained to recognize the signs and symptoms of this disease before it is too late. 


Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in managementDiagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907

Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ductsTransl Gastroenterol Hepatol. 2021;6:22. doi:10.21037/tgh-2020-03