Part 2 of a 3-part series

Henry Lin, MD, MBA
Henry Lin, MD, MBA

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with variable clinical manifestations. Common organ systems involved in ALGS include the liver, heart, kidneys, vascular, skeletal, and eye. In this article, we will review common clinical presentations and management considerations for renal, skeletal, ocular, and vascular involvement in ALGS.

Read Part 1 of the series: Managing the Clinical Manifestations of ALGS: Hepatic and Cardiac Considerations


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Renal

Clinical Manifestations

The prevalence of renal involvement in ALGS has been reported to range between 23% and 74% and may be more prevalent in individuals with NOTCH2 mutations. Both structural and functional renal abnormalities along with acquired renal disease have been observed in ALGS. Structural renal anomalies include small kidneys, solitary kidney, dysplastic kidneys, ectopic kidney, cystic kidneys, and bifid pelvis.

Studies suggest renal dysplasia is the most commonly observed renal abnormality in ALGS.  Renal dysplasia occurs when the internal kidney structures do not develop normally, leading to impairment of urine flow with subsequent collection of urine and cyst formation. Dysplasia can affect one or both kidneys and individuals with mild dysplasia may not have impairment of renal function. 

Functional renal anomalies seen in ALGS include renal insufficiency, renal tubular acidosis, tubulointerstitial nephropathy, juvenile nephronophthisis, and glomerular lipidosis. Symptoms of renal tubular acidosis (RTA) vary by type. In type 1 and type 2 RTA, symptoms related to low potassium and bicarbonate level include weakness and arrhythmias. Symptoms of type 4 RTA are related to high potassium and low bicarbonate level and include fatigue, muscle weakness, abdominal pain, and weight loss.

Renal vascular disease such as arterial stenosis has also been reported in ALGS.

Evaluation

All patients with ALGS should have a baseline ultrasound of the kidneys to assess for structural anomalies. In addition, a baseline evaluation of renal function consisting of a creatinine and blood urea nitrogen level should be checked and followed annually. Renal function can be calculated using the creatinine or a cystatin C level to estimate the glomerular filtration rate.  

In addition to renal labs and imaging, routine monitoring of blood pressure is suggested. If hypertension is noted, a more thorough renal assessment should be considered, as individuals with ALGS may have vascular involvement and renal arterial stenosis can cause elevated blood pressure. Growth parameters should also be monitored, as renal tubular acidosis can present with growth failure in children. 

Given the increased prevalence of NOTCH2 mutations in ALGS renal disease, screening for mutations in NOTCH2 should be considered for individuals with ALGS and no identified JAG1 mutation.

Management

The management of renal disease is targeted to the specific anomaly or disease. In general, progression to chronic kidney disease and need for kidney transplant is rare.

In ALGS patients who have received a liver transplant, close monitoring of renal function is necessary while on calcineurin inhibitors used as primary immunosuppression post-transplant. The risk of nephrotoxicity from calcineurin inhibitors may be increased in individuals with abnormal kidneys.

Skeletal

Clinical Manifestations

A wide range of skeletal findings has been reported in ALGS, with butterfly vertebrae being the most common. Butterfly vertebrae are formed when there is incomplete fusion of the anterior vertebral arch, leading to a “butterfly” appearance on x-ray. Butterfly vertebrae are typically asymptomatic and can also be found in syndromes such as Kabuki syndrome or VACTERL association (vertebral anomalies, anorectal malformations, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb defects).

Cholestasis can also contribute to the presence of skeletal involvement in ALGS, as poor bile flow may limit fat-soluble absorption of vitamins including vitamin D and lead to poor bone mineral density. Individuals with low bone density are at risk for osteopenia and pathologic fractures, and fractures may occur with minimal trauma. Other skeletal anomalies reported in ALGS include radioulnar synostosis, clinodactyly, and shortened distal phalanges.

Evaluation

X-ray of the spine is a common diagnostic tool to assess for butterfly vertebrae. Routine monitoring of bone density such as with a dual-energy x-ray absorptiometry (DEXA) scan is recommended. Baseline levels of vitamin D and calcium can help assess bone health.

Management

The management of skeletal involvement is mostly focused on bone health. Butterfly vertebrae do not require specific management. Individuals with a history of fractures or low bone density should have vitamin D levels checked and supplemented if low.

Ocular

Clinical Manifestations

A wide range of ophthalmologic findings has been reported in ALGS, including abnormalities of the cornea, retina, iris, and optic disc.

Posterior embryotoxon is the most common ophthalmologic finding in ALGS but is also found in patients with 22q11 syndrome as well as in around 15% of the general population. Posterior embryotoxon, or Axenfeld anomaly, is a defect of the anterior chamber of the eye in which there is a thickened and anteriorly displaced Schwalbe’s line. It can be associated with abnormal fundus pigmentation and does not affect visual acuity.

Retinal pigmentary changes are another common ocular finding in ALGS. Optic disc anomalies in ALGS include disc atrophy, hypoplasia, and drusen. Optic disc drusen are proteinaceous deposits in the optic nerve that can become calcified with age, which can cause pseudopapilledema and may lead to visual field loss. Drusen occurs from dysplasia that affects vascular supply to the optic disc.

In people with ALGS liver disease who are cholestatic, fat-soluble vitamin deficiencies may occur. Vitamin A deficiency can cause xerophthalmia, with symptoms including keratomalacia, xerosis, and night blindness.

Evaluation

In people with ALGS, a baseline evaluation by an ophthalmologist should be performed to assess for ocular involvement. A slit lamp exam can be used to diagnose posterior embryotoxon; on exam, the Schwalbe’s line is found to be anterior to and concentric with the limbus. An ocular ultrasound may be indicated to assess for optic disc drusen. 

Management

The management of ocular findings in ALGS is based on the specific abnormality. Individuals with ocular manifestations should be followed by an ophthalmologist with routine assessments, as, in rare instances, anterior chamber defects can be associated with glaucoma. No specific treatment is needed for posterior embryotoxon.

Vascular

Clinical Manifestations

Vascular anomalies of the liver, heart, kidneys, and brain have been associated with ALGS, with peripheral pulmonary artery stenosis being a common vascular anomaly in ALGS. Other vascular anomalies which have been noted in ALGS include cerebrovascular anomalies, aortic aneurysm, coarctation of the aorta, renal artery stenosis, and anomalies in the celiac trunk and hepatic vasculature. 

Cerebrovascular anomalies can lead to cerebrovascular accidents or intracranial hemorrhage and include moyamoya disease as well as aneurysms of the middle cerebral artery, basilar artery, and carotid artery. Moyamoya disease is a progressive stenosis or occlusion of the intracranial arteries including the carotid artery.

The clinical presentation from cerebrovascular anomalies is variable and may include nonspecific symptoms such as headache.  Hemiparesis and slurred speech have also been reported. Many individuals with cerebrovascular anomalies are asymptomatic. However, there is a risk of ischemic and hemorrhagic infarctions with cerebrovascular malformations, and intracranial hemorrhage remains a significant cause of morbidity in ALGS.

Evaluation

A neurologic evaluation should be performed on any individual presenting with neurologic signs or symptoms. Given the risk of intracranial hemorrhage with cerebrovascular anomalies, a baseline screening MRI angiography of the head is recommended to screen for cerebrovascular anomalies. If an individual is asymptomatic, the head MRI may be delayed until the individual is old enough to lay still during the MRI without the need for sedation.  However, a head MRI should be obtained prior to any major surgery. 

Management

The management of vascular anomalies is based on the underlying defect.

References

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Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. doi:10.1002/hep.510290331

Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999;106:330-337. doi:10.1016/S0161-6420(99)90072-6

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Kamath BM, Podkameni G, Hutchinson AL, et al. Renal anomalies in Alagille syndrome: a disease-defining feature. Am J Med Genet A. 2012;158A(1):85-89. doi:10.1002/ajmg.a.34369

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