GATA6 Mutation: A Rare Genetic Cause of Hepatobiliary Disease
The patient was the second child of healthy and nonconsanguineous parents. They had a previous term male baby with a complex cardiac anomaly who died, during the neonatal period, following cardiac surgery.
Our patient was born at 39 weeks gestation after an uneventful pregnancy (marked intrauterine growth restriction). Immediately after birth, the patient was admitted to neonatal intensive care because of antenatal diagnosis of congenital heart defect. Postnatal echocardiography confirmed a complex form of double-outlet right ventricle with a doubly committed ventricular septal defect and valvular pulmonary stenosis. The patient did not require ventilatory support and remained stable from the cardiovascular point of view.
From the second week of life, the patient was noted to have conjugated hyperbilirubinemia, pale stools, and failure to thrive. Her liver function tests were as follows: total bilirubin of 48 to 76 μmol/L, conjugated bilirubin of 41 to 61 μmol/L (normal <21 and <12 μmol/L, respectively), γ glutamyl transferase >300 IU/L (normal <115 IU/L); alkaline phosphatase and transaminases were normal. The patient had preserved hepatic synthetic function. On physical examination, the patient was jaundiced, without any obvious dysmorphic features or hepatosplenomegaly or ascites. Screening investigations for neonatal cholestasis were normal: α-1-antitrypsin levels and phenotype, galactosaemia and tyrosinaemia type 1 screening tests, viral serologies, and so on. Ophthalmological evaluation revealed posterior embryotoxon bilaterally. Her vertebrae were normal. Genetic study for Alagille syndrome was negative. Antenatal amniocentesis showed a normal karyotype with negative fluorescent in-situ hybridisation for DiGeorge and Trisomies 13, 18, and 21. An abdominal ultrasound failed to identify the gallbladder despite a 4-hour fast. The liver was normal without biliary dilatation seen and normal hepatic vessels. The spleen was normal. A hepatobiliary iminodiacetic acid scan showed good hepatic uptake, absence of the gallbladder, and no hepatic excretion. Liver biopsy demonstrated paucity of intrahepatic bile ducts and severe cholestasis.
The patient was noted to have neonatal diabetes and exocrine pancreatic insufficiency (faecal elastase <15 μg/g) controlled with pancreatin.
Thyroid function tests revealed low free T4 and free T3 levels, (8.7 pmol/L and 2.2 pmol/L, respectively) with normal thyroid stimulating hormone, consistent with secondary hypothyroidism or “sick thyroid syndrome” instead of primary hypothyroidism.
The presence of neonatal cholestasis associated with congenital heart disease and diabetes prompted us to do a genetic study, which revealed a heterozygous mutation, (c.899_902dup), in GATA6 gene. The same mutation was found in her mother. Genetic study could not be performed in her father (refused genetic testing) or in her deceased brother.
Cardiac repair was attempted at 4 months of age, but was impossible, as the tricuspid valve has remained relatively small. In addition, the pulmonary artery pressure was too elevated to consider cavopulmonary anastomosis.
At 6 months of age, the patient is not jaundiced, is passing normal-coloured stools, and is thriving. The patient is developmentally delayed probably because of prolonged hospitalisation (normal cranial ultrasound scans), but possible influence of GATA6 mutation cannot be excluded. The patient is on a continuous insulin infusion pump, and has normal thyroid function tests on a small dose of thyroxine. Whether her hypothyroidism is permanent or a result of the GATA6 mutation is yet to be elucidated.