Alagille Syndrome (ALGS)


Alagille syndrome (ALGS) is an autosomal dominant disease caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) gene.1,2 The reported incidence for ALGS is 1 in 30,000 live births.1

Alagille syndrome is a multisystemic disease affecting several organ systems such as the liver, face, eyes, heart, and skeleton.3 Many reports have highlighted vascular and renal damages as consequences of the perturbations in the Notch signaling pathway.4,5 Following these findings, the clinical criteria for ALGS were extended and now include 7 main organ systems.3 Patterns and degrees of organ damage are variable even between patients that share the same mutation.3

Hepatic Features

Hepatic manifestations such as paucity of biliary ducts, conjugated hyperbilirubinemia with high gamma-glutamyl transferase (GGT), and liver failure are classical clinical features of ALGS.1 During the first year of life, infants typically show cholestasis and normal synthetic liver function. In newborns, a liver biopsy is not always compatible with duct paucity and may reveal ductal proliferation instead, leading to a misdiagnosis of ALGS as biliary atresia.1 

Cholestasis may lead to fat-soluble vitamin deficiency (FSVD) and consequently vitamin K deficiency and coagulopathies.1,6 In addition to causing medical complications such as bleeding, FSVD can also lead to a high risk of fractures and pruritus. Pruritus is the most significant symptom after cholestasis and is correlated with high levels of serum bile salts.3 It develops early in infancy, may be associated with jaundice and can cause skin disfigurement from excoriations.1,3 Scratch marks are typically found on the trunk, ears, and feet.3

In addition to FSVD, cholestasis can also lead to the formation of cutaneous xanthomas on the hands and knees. These lesions occur in a clinical scenario of hypercholesterolemia, which is commonly found in patients with ALGS. These manifestations can resolve over time when cholestasis is controlled.1 

Liver transplantation may be required in about 15% of patients with ALGS and is typically the result of cholestasis complications in early childhood.3,7 Hepatomegaly and splenomegaly are also evident in at least 70% of patients with ALGS.3

Cardiac Features

About 90% to 97% of patients with ALGS present with cardiac manifestations.7 These range from heart murmurs to structural defects such as septal anomalies. Cardiac findings are predominant on the right side, with the pulmonary vasculature also affected.8 The most typical cardiac finding is pulmonic stenosis, while tetralogy of Fallot can be found in 7% to 16% of patients. Complex cardiac defects result in the early death of 15% of patients with ALGS.7

Facial Features

About 70% to 96% of ALGS patients show particular facial features that are accentuated with age.2,3 These features are less prevalent in patients with NOTCH2 mutations.1 Distinct facial findings include an inverted triangular face with a high prominent forehand with frontal bossing or flattening.1 Patients also exhibit a pointed chin and a straight nose with a bulbous tip.3 Deep-set eyes and hypertelorism are also distinctive.1.3

Ocular Features

Posterior embryotoxon is the most common ocular finding, occurring in 78% to 89% of patients with ALGS.1,7 There are other ocular manifestations, such as Axenfield-Rieger anomaly, optic disc drusen, and retinal pigmentary changes induced by ALGS.1 These changes do not normally affect vision quality.2

Skeletal Features

There are many vertebral defects associated with ALGS, with the butterfly vertebrae being the most common one.1-3 In these vertebral bodies, the anterior arches are not fused, splitting the vertebrae in the sagittal plane into hemivertebrae.2 Butterfly vertebrae may be present in up to 87% of patients with ALGS.9

Other skeletal manifestations include an increased risk of long bone pathological fractures.1,3 These fractures most commonly occur in the lower extremities and result from different factors such as cholestasis, vitamin D deficiency, and existing bone defects that occur due to the perturbation of the Notch signaling pathway.2,3 Square-shaped proximal fingers with a tapering of the distal phalanges and an extradigital flexion crease, ulnar shortening, and temporal bone defects may be observed.2,10 

Renal Features

The prevalence of renal manifestations in patients with ALGS is estimated to be 20% to 73%.9 Structural and functional anomalies such as renal cysts, renal dysplasia, and urinary obstruction can be observed.1,3 This significant prevalence has supported renal involvement as a disease-defining feature.2,3,5 The evolution to a chronic renal disease or the need for a renal transplant is rare.3

Vascular Features

Vascular manifestations ranging from cerebral infarcts to complicated intracranial bleeding are responsible for death in 25% to 50% of patients.3,7 The vasculature beyond the central nervous system (CNS) and the pulmonary vessels may be also affected. Renovascular defects have been reported, as well as manifestations in subclavian, hepatic, and mesenteric vasculature.11,12 Aneurysms and coarctation of the aorta may occur, and studies correlate these with intracranial lesions.13 Defects of the abdominal vessels are common and may complicate a liver transplant.14

References

  1. Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
  2. Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641. doi:10.1016/j.cld.2018.06.001
  3. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907
  4. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. 1999;29(4):431-437. doi:10.1097/00005176-199910000-00011
  5. 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
  6. Kriegermeier A, Wehrman A, Kamath BM, Loomes KM. Liver disease in Alagille syndrome. In: Kamath B, Loomes K, eds. Alagille Syndrome. Springer, Cham; 2018;49-65. Accessed June 24, 2021.
  7. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. doi:10.1002/hep.510290331
  8. McElhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation. 2002;106(20):2567-2574. doi:10.1161/01.cir.0000037221.45902.69
  9. Subramaniam P, Knisely A, Portmann B, et al. Diagnosis of Alagille syndrome—25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr. 2011;52(1):84-89. doi:10.1097/MPG.0b013e3181f1572d
  10. Kamath BM, Loomes KM, Oakey RJ, Krantz ID. Supernumerary digital flexion creases: an additional clinical manifestation of Alagille syndrome. Am J Med Genet. 2002;112(2):171-175. doi:10.1002/ajmg.10628
  11. Salem JE, Bruguiere E, Iserin L, Guiochon-Mantel A, Plouin PF. Hypertension and aortorenal disease in Alagille syndrome. J Hypertens. 2012;30(7):1300-1306. doi:10.1097/HJH.0b013e3283531e1f
  12. Bérard E, Sarles J, Triolo V, et al. Renovascular hypertension and vascular anomalies in Alagille syndrome. Pediatr Nephrol. 1998;12(2):121-124. doi:10.1007/s004670050418
  13. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;109(11):1354-1358. doi:10.1161/01.CIR.0000121361.01862
  14. Kohaut J, Pommier R, Guerin F, et al. Abdominal arterial anomalies in children with Alagille syndrome: surgical aspects and outcomes of liver transplantation. J Pediatr Gastroenterol Nutr. 2017;64(6):888-891. doi:10.1097/MPG.0000000000001538

Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.

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