Physical Examination
Presentation of Alagille syndrome (AS) varies. Some patients are diagnosed after prolonged neonatal jaundice or when liver biopsy findings reveal paucity of intrahepatic bile ducts. Others may be diagnosed during evaluation for right-sided heart disease. Some individuals are diagnosed by careful examination after an index case is identified in the family.
Nutrition and growth
Children often present with poor linear growth. Altered longitudinal growth is attributed to wasting or inadequate intake, and an element of growth hormone resistance may also be present. [8] Studies to assess the impact of higher doses of growth hormone on linear growth in patients with Alagille syndrome are currently underway.
Head and neck
Commonly associated facial features include broadened forehead, pointed chin, and elongated nose with bulbous tip. Characteristic facial features may not be obvious during infancy but may become more apparent as the child ages.
Ophthalmologic
Ocular abnormalities are common. [9] The most frequent ophthalmologic finding is a posterior embryotoxon, which was observed in more than 75% of patients in one large series conducted by Emerick et al. [10] Some of these patients may also have the Axenfeld anomaly (ie, iris attachment to Descemet membrane).
Other findings reported include retinitis pigmentosa, pupillary abnormalities, and anomalies of the optic disc.
Rock et al reported nine cases of bilateral papilledema in children with Alagille syndrome; five of the cases were associated with intracranial hypertension. [11]
Cardiovascular
Nearly all patients have cardiac murmurs. The most common cardiac lesions are stenoses within the pulmonary tree (peripheral pulmonic stenosis) with or without other structural lesions.
Hemodynamically significant lesions include atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot, patent ductus arteriosus (PDA), and pulmonary atresia (PA). Significant intracardiac lesions place patients with Alagille syndrome at increased mortality risk.
Recent data have reported an association between Wolff-Parkinson-White syndrome in a subset of patients with Alagille syndrome. [12]
Hepatic
Hepatic disease is a key feature of Alagille syndrome. Most infants present with cholestatic jaundice. Hepatosplenomegaly is common.
Elevations in serum bile acids often result in severe pruritus and xanthomas (hypercholesterolemia). Fat-soluble vitamin deficiencies, including coagulopathies and rickets, are frequent.
Skeletal
Abnormalities of the vertebrae, ribs, and hands are frequently associated with Alagille syndrome. Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick et al in a large series of patients with Alagille syndrome. [10]
Other isolated anomalies include rib anomalies and shortening of the radius, ulna, and phalanges.
Neurologic
Mild developmental delay and mental retardation are reported in some children with Alagille syndrome. If noted during the physical examination, diminished deep tendon reflexes should direct the clinician to exclude vitamin E deficiency.
Renal
Occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis may present with signs and symptoms of chronic hypertension. Data from one study show that renal involvement was present in 73 (39%) of 187 of the evaluable pediatric Alagille syndrome patients studied, with renal dysplasia being the most common anomaly. The researchers suggested that renal involvement be considered a defining criterion for Alagille syndrome.
Recent data suggest a role for NOTCH2 and JAG1 in proximal nephron structures/podocytes, which contribute to the observed phenotypes of renal dysplasia and proteinuria seen in Alagille syndrome; renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. [13, 14]
Vascular
Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al. [15] These lesions included basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, Moyamoya disease and aortic aneurysms, coarctation of the aorta, and renal artery stenosis.
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Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).
