Alagille syndrome, a genetic disorder inherited in an autosomal dominant manner, typically involves pathology in multiple organs, including the liver, heart, skin, and bone. Liver disease usually receives the most attention because unresolved liver disease often requires liver transplantation, but cardiac disease is also a significant part of the Alagille syndrome phenotype.
“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 Diagnostics. “The highest mortality rate was reported at 75% in patients with [tetralogy of Fallot] and pulmonary atresia, and 34% in [patients with tetralogy of Fallot] alone.”
The cardiac anomalies most commonly associated with Alagille syndrome include congenital heart disease. Studies indicate that around 76% of patients present with hypoplasia/stenosis of the branch pulmonary arteries. In addition, tetralogy of Fallot is a relatively common cardiac finding in patients with Alagille syndrome. Generally, greater cardiac involvement translates to a greater mortality risk.
The liver and cardiac disease typically seen in patients with Alagille syndrome require specialist care, since both medical and surgical disciplines are involved.
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An Unusual Pediatric Case of Alagille Syndrome
In Open Access Case Report, Bhende and colleagues presented the case study of a pediatric patient who had significant cardiac and skeletal anomalies due to Alagille syndrome. The case detailed a 4-year-old girl who had moderate ostium secundum atrial septal defect and branch pulmonary artery stenosis, resulting in acyanotic congenital heart disease.
The patient was also observed to have the typical facial features seen in patients with Alagille syndrome—frontal bossing, deep-set eyes, triangular facies, a pointed chin, and joint laxity—as well as delayed mental development and poor speech.
Ocular tests revealed posterior embryotoxon and, in the right eye, mild pigmentary retinopathy. A chest x-ray revealed a “butterfly presentation” (abnormal segmentation in the T5 vertebrae), and the patient had a history of recurrent infections.
Cardiac computed tomography (CT) scans were conducted to investigate the extent of cardiac disease. Hypoplastic main right and left pulmonary arteries could be observed; the McGoon ratio was 1.65 and the Nakata index was 169.36 mm2/m2.
“Right ventricular pressure was significantly elevated with hypertrophy and dilatation of the right atrium and the right ventricle with normal biventricular function,” Bhende et al wrote.
Surgeons opted for a bilateral branch pulmonary artery plasty with a glutaraldehyde-treated pericardial patch. In addition, the patient underwent direct closure of the atrial septal defect, leaving a patent foramen ovale.
Post-surgery, she was on mechanical ventilation with adrenaline and milrinone support. She was extubated on the third day. After checks on her cardiac function, she was discharged in stable condition.
Treating a Multisystem Disease
Alagille syndrome falls squarely in the category of a multisystem disease because it can affect multiple organs of the body, requiring multidisciplinary care. However, multisystem disease may not be present upon presentation, and certain organ(s) can be more heavily involved than others.
“[Alagille syndrome] may present with hepatic complications or cardiac anomalies in isolation; therefore, it is important to not miss out on the diagnosis and to have a higher clinical suspicion for [Alagille syndrome],” Bhende et al cautioned.
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In the case study presented, the patient’s primary problem was her cardiac disease. In fact, the entire management process undertaken by her physicians has been focused on managing her cardiac anomalies; there was no mention of liver disease or the treatment of liver disease.
In patients with Alagille syndrome with cardiac disease, the right side of the heart tends to be more affected than the left side. The most commonly reported sign upon imaging is branch pulmonary artery stenosis or hyperplasia. Should tetralogy of Fallot be found in patients with Alagille syndrome, the condition tends to be more severe than in the general population and is likely to be associated with pulmonary atresia.
Because various organs can become diseased in Alagille syndrome, it is all the more important that physicians carry out a thorough investigation of a patient with Alagille syndrome upon presentation. In addition, follow-ups should also consist of asking patients if they have noticed any new symptoms of the disease.
Alagille syndrome is indeed a difficult disease to treat by any one medical team. However, if the disease is broken down according to the systems affected, the involvement of appropriate specialists makes care much more manageable. Whether multiple organs are affected or primarily just one (such as in the case study), physicians should work together to ensure that the patient receives optimal care.
Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. Published November 6, 2020. doi:10.3390/diagnostics10110907
Bhende VV, Majmudar HP, Sharma TS, Pathan SR, Mehta DV. Nonhepatic Alagille syndrome associated with predominant cardiovascular anomalies: a rare case. Cureus. 2021;13(8):e17429. doi:10.7759/cureus.17429