Alagille syndrome

Alagille syndrome is a very rare genetically determined congenital disease. It occurs in approximately 1 out of 70,000–100,000 live‑born children. It affects several organs — the liver, heart, kidneys, skeleton, and eyes. The form of this syndrome is highly variable, and the severity spans a wide range.

Causes:

The cause is a genetic mutation of the JAG1 gene (responsible for 88% of cases) or the NOTCH2 gene. The mutation arises during the development of the individual de novo, or it is inherited from the parents in an autosomal dominant manner.
The mutation damages a gene responsible for the proper formation of the internal structure of the body during fetal development. For this reason, numerous deformities and defects of tissues and organs result from this disorder. The occurrence of the mutation or inheritance is the same for males as for females.

Symptoms:

Already in small children during the first four months, it is possible to diagnose jaundice, itching of the skin (pruritus), various stages of liver damage, cholestasis (due to a lack of bile ducts and the inability of bile to drain). In about 90% of patients with Alagille syndrome, the absence of bile ducts for bile drainage into the intestine is diagnosed. Stool is usually pale, urine has a dark color. Newborns suffer from digestive disorders — especially of fats — impaired absorption of vitamins (A, D, E, K) and micronutrients, and the resulting symptoms (bone disorders, impaired vision, etc.). Newborns fail to thrive, suffer from malabsorption, or disturbances of internal homeostasis. Mild delayed psychomotor development may be present. Liver damage may progress to cirrhosis and liver failure (about 15% of patients with this diagnosis). The pancreas also has insufficient function (both enzymatic and hormonal).

Already in newborns, a heart murmur can be clinically detected. Heart damage occurs across a wide range — from a benign (insignificant) heart murmur to severe and life‑threatening heart defects that must be treated surgically. Present may be ventricular septal defects, narrowing of the pulmonary arteries to various degrees, Tetralogy of Fallot, and rhythm disturbances — WPW syndrome.
Heart damage may cause bluish discoloration of the lips and face during increased oxygen demand, during exertion, and in severe defects even at rest.

A typical symptom of Alagille syndrome is posterior embryotoxon, which is a thickened ring around the cornea, visible also with the naked eye or during an eye examination. Visual function is usually not impaired.

Individuals with Alagille syndrome have typical facial features — hypertelorism (deep‑set and widely spaced eyes), low‑set ears, a prominent pointed chin, and a broad forehead.

Other anomalies include kidney anomalies (impaired renal function, small kidneys), pancreatic insufficiency (reduced function), vascular anomalies (they may cause rupture of vessels, e.g., in the brain, and subsequent rupture and bleeding into the brain).

Diagnosis:

Diagnosis is established based on clinical symptoms, the patient’s medical history, laboratory diagnostics, and imaging methods that precisely determine the extent of organ damage. A physician suspects Alagille syndrome if 3 out of 5 symptoms are present — liver damage, congenital heart defects, skeletal abnormalities, eye abnormalities in combination with the presence of reduced bile ducts and/or typical facial features.

A liver biopsy can detect a reduction in bile duct structures, which is present in 90% of patients.

Genetic testing establishes the final diagnosis, confirming the presence of gene mutations.

Treatment:

Treatment is highly specific for each patient. It is necessary to identify organ abnormalities, cardiac defects, liver damage, and kidney impairment.

A cardiologist determines the need for surgical treatment. Long‑term follow‑up by a gastroenterologist is necessary, who administers medications that improve bile drainage into the intestine, antihistamines due to pruritus, hepatoprotective therapy, supplementation of nutrients and vitamins, management of malabsorption, administration of easily digestible formulas, pancreatic enzymes, etc.

• typické črty tváre – široké čelo, prominentná brada u dospelých (prognatia), nízko zasadené uši, oči hlboko a ďaleko od seba (hypertelorizmus), špicatá brada
• kongenitálne srdcové defekty - defekt komorového septa, fallotova tetralógia, stenóza pľúcnych tepien
• poškodenie pečene v rôznom rozsahu (asymptomatické, ľahké až ťažké poškodenie - cirhóza pečene)
• biopsia pečene - nedostatok žlčových kanálov
• hromadenie žlče a kyselín v žlčových cestách (cholestáza)
• hromadenie bilirubínu, cholesterolu v tkanivách
• žltačka, svrbenie kože (pruritus)
• porucha trávania tukov, vitamínov (A,D,E,K), malabsorbcia
• slabé priberanie, slabý rast u novorodencov, neprospievanie
• xantómy (vačky na koži plné cholesterolu)
• posteriorny embryotoxón (zhrubnutý prstenec okolo rohovky)
• obličkové abnormality (malé obličky), poškodenie renálnej funkcie
• pankreatická nedostatočnosť (pankreatopatia)
• vaskulárne abnormality (riziko ruptúry ciev v mozgu a následne krvácanie do mozgu)
• skeletálne abnormality - v oblasti stavcov
• oneskorenie psychomotorického vývoja a kognitívnych funkcií