Alagille Syndrome (ALGS)


Alagille syndrome (ALGS), also known as arteriohepatic dysplasia or Alagille-Watson Syndrome, can affect numerous systems of the body.1 It is caused by genetic mutations of the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes that affect the Notch signaling pathway, a highly conserved system important for embryonic development.2 Although the disease follows an autosomal dominant inheritance pattern, it exhibits reduced penetrance and variable expressivity, which can lead to variations in clinical features.

Liver Effects in ALGS

The most consistent clinical feature of ALGS is bile duct paucity.2 The lack of sufficient bile ducts leads to chronic cholestasis with possible jaundice and hyperbilirubinemia, depending on the severity. Bile duct paucity appears to increase as infants age, with it being more prevalent in children over 6 months of age compared to those who are younger.1 Cholestasis can also lead to pruritus and xanthomas that can severely impact the quality of life for children.2 Patients may experience increased levels of alkaline phosphatase and gamma glutamyltransferase, which can damage bile ducts as well.2 Progressive liver disease that can ultimately lead to cirrhosis and liver failure has also been seen in some patients.1

ALGS Tetralogy of Fallot
Tetraology of Fallot in ALGS.

ALGS and Cardiovascular Systems

Another very common feature of patients with ALGS is congenital cardiovascular anomalies. A study of 200 ALGS patient records found evidence of cardiovascular issues in 94% of patients either through imaging (n = 150) or the presence of peripheral pulmonary stenosis (PPS) murmur in patients with normal imaging or without imaging (n = 37).3 The most common feature found in 76% of patients was PPS. The second most common, found through imaging in 23 patients,3 was tetralogy of Fallot — the combination of PPS, ventricular septal defect, displaced aorta, and right ventricular hypertrophy.4 Other types of abnormalities observed included aortic septal defects and aortic stenosis.

Alagille syndrome also appears to cause vascular issues outside of the heart. A chart review study of 268 patients with ALGS found that 25 (9%) had noncardiac vascular anomalies. These anomalies included a number of aneurysms at locations throughout the body, coarctation of the aorta, renal artery stenosis, and moyamoya disease, a progressive intracranial artery disease.5

Skeletal Abnormalities in ALGS

Abnormalities of the skeletal system are also relatively common in patients with ALGS. The most commonly reported skeletal abnormality, occurring in as high as 66% of patients,6 is a condition known as “butterfly” vertebrae, characterized by two lateral hemivertebrae with a central cleft in the sagittal plane, which is visible on radiographic imaging.7 Other features that may be present in the axial skeleton include spina bifida occulta, narrowing of the lumbar interpedicular distances, fusion of vertebrae, and an absence of the 12th rib.1

Synostosis has also been reported in cranial bones,8 as well as between the radius and ulna.9 Shortening of the ulna or distal phalanges has also been exhibited by patients.10 Fingers may have a fusiform shape with tapering at the distal ends.1 Patients with ALGS may also present with osteoporosis, leading to a higher risk of fractures, especially in the lower limbs.2

Facial Features of ALGS Patients 

Patients with ALGS tend to have particular facial features. These characteristics can include prominent foreheads, triangular-shaped chins, orbital hypertelorism, deep-set eyes, and narrow, upward slanting palpebral fissures.1 These features can be highly variable in patients, however, making them less useful for diagnosis.

Ocular Effects of ALGS

Alagille syndrome appears to affect structures of the eye as well. The most common ocular feature found in patients is posterior embryotoxon — a prominent Schwalbe’s ring on the edge of the iris.1 Several other anomalies may also be present in patients, including Axenfeld anomaly, microcornea, congenital macular dystrophy, keratoconus, band keratopathy, exotropia, unusual iris stromal hypoplasia patterns, cataracts, a shallow anterior chamber, retinal fundus hypopigmentation, optic disc drusen,1 mesodermal dysgenesis, corneal arcus, lens opacity, and granularity of the retinal pigment.2

Renal Effects of ALGS

A retrospective study investigated the renal involvement of ALGS in 466 patients. The study found that the most common renal symptoms included renal dysplasia, renal tubular acidosis, vesicoureteral reflux, and urinary obstruction.11 Chronic renal failure and end-stage renal disease were also reported, but much less frequently. 

Mixed Data on Pancreas Effects

Some initial clinical reports indicated that pancreatic insufficiency may be an issue in patients with ALGS. These studies reported high rates of steatorrhea, decreased responses to secretin-pancreozymin stimulation testing, and an increased rate of growth in patients given pancreatic enzyme supplements.2,12 More recent work, however, found that fecal levels of elastase-1 and lipase were normal and did not indicate pancreatic insufficiency.12

Growth and Nutrition

Patients with ALGS are often smaller in stature and lighter in weight than their age-matched counterparts in the general population.2 These issues are most likely related to problems of dietary malabsorption due to cholestasis, but they may also be related to other issues which have been described in the literature, such as hypothyroidism and growth hormone insensitivity.1

Neural Development in ALGS

Neurological deficits such as mental retardation with low IQs and motor delays may be other symptoms of ALGS.2 These may be impacted by chronic cholestasis as well as insufficient nutritional absorption, but may also indicate a role of the Notch pathway in neurodevelopment.2 Chronic symptoms such as pruritus and xanthomas, as well as characteristic facies, may affect a patient’s self-image and ultimately their mental health.2

A questionnaire study compared health-related quality of life for patients with ALGS with a normative population as well as those with a few other childhood disorders.13 The study found that ALGS patients, when compared to the normative population, had a higher prevalence of mental health diagnoses (18% vs 5-10%), attention problems (32% vs 19%), and depression (10% vs 5%).13  The authors attributed the depression to psychosocial factors of the disease including short stature, delayed maturation, pruritus, and physical disabilities from heart, liver, or kidney disease.13

References

  1. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
  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. 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
  4. Tetralogy of Fallot. National Organization for Rare Disorders. Accessed June 17, 2021. 
  5. 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.A4
  6. Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatr Radiol. 2002;32(2):114-119. doi:10.1007/s00247-001-0599-x
  7. Katsuura Y, Kim HJ. Butterfly vertebrae: a systematic review of the literature and analysis. Global Spine J. 2019;9(6):666-679. doi:10.1177/2192568218801016
  8. Kamath BM, Stolle C, Bason L, et al. Craniosynostosis in Alagille syndrome. Am J Med Genet. 2002;112(2):176-180. doi:10.1002/ajmg.10608
  9. Ryan RS, Myckatyn SO, Reid GD, Munk P. Alagille syndrome: case report with bilateral radio-ulnar synostosis and a literature review. Skeletal Radiol. 2003;32(8):489-491. doi:10.1007/s00256-003-0651-z
  10. Berrocal T, Gamo E, Navalón J, et al. Syndrome of Alagille: radiological and sonographic findings. A review of 37 cases. Eur Radiol. 1997;7(1):115-118. doi:10.1007/s003300050122
  11. 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
  12. Gliwicz D, Jankowska I, Wierzbicka A, Miśkiewicz-Chotnicka A, Lisowska A, Walkowiak J. Exocrine pancreatic function in children with Alagille syndrome. Sci Rep. 2016;6:35229. doi:10.1038/srep35229
  13. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51(6):759-765. doi:10.1097/MPG.0b013e3181ef3771

Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.

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