Jos Jansen

38 Chapter 2 parents. As a neonate, individual F4-II1 showed neonatal jaundice. Progressive cholestatic liver disease was diagnosed at an early age. Due to progressive liver failure, sibling F4-II1 underwent a liver transplantation at the age of three years and ten months, and sibling F4-II2 at the age of eight years. Unfortunately, the transplant of sibling F4-II1 was rejected twice, and he died at the age of nine years. Both siblings showed mild dysmorphic features and individual F4-II1 had a mild PMD. They showed elevated AT and ALP during several check-ups (F4- II1: AST 192–669 U/l, ALT 83–308 U/l, ALP 702 U/l; F4-II2: AST 98–422 U/l, ALT 98–178 U/l, ALP 710–985 U/l). Ceruloplasmin was never measured. After liver transplantation, individual F4-II2 is doing well. Among other parameters, her AT and CDG profile have normalized. Individual F5-II1 (female, born in 2014, died after seven months) was the only child of non-consanguineous Portuguese parents. Jaundice was noticed since the first day of life. At five months, jaundice persisted and she developed hepatosplenomegaly, failure to thrive, redundant skin, poor muscle volume, and generalized hypotonia. There were no signs of PMD. Her parents refused a liver biopsy. Intermittent episodes of hypoglycemia and hyperammonemia ensued. Subsequently, she developed progressive cholestatic liver disease (bilirubin 41.3 mg/dl, 40% conjugated) and liver failure. Investigation showed increased ATs (AST 207–972 U/l, ALT 48–153 U/l) and ALP (850–1,031 U/l). Additional biochemical analysis revealed hypercholesterolemia (431 mg/dl) and elevated LDL-C (314 mg/dl), abnormal coagulation factors (low FVII and high FVIII, INR 0.79–3.0), and anemia (Hb 7 g/dl) with acanthocytes and 7% reticulocytes. Interestingly, a bone marrow biopsy showed dyserythropoiesis, some lipidic histiocytes, and erythrophagocytosis. Later on, generalized cell vacuolization and few erythroblasts with perinuclear deposition of iron were seen. CDG screening revealed a type 2 pattern. Liver transplantation was not attempted due to rapid deterioration with multi-organ failure and encephalopathy. She died at the age of seven months. Postmortem liver analysis revealed severe cholestatic hepatitis with complete septal fibrosis and cirrhosis.