The patient, a male of white European descent with British and German ancestry, was admitted for evaluation of liver transplantation at age 20 years. Beginning at approximately 9 months of age, he presented with recurrent episodes of PALF. His mother found him icteric after febrile illness. Between these episodes, liver enzymes were normal or exhibited only mild elevations. The patient's liver episodes ceased at 2 years of age but showed hepatosplenomegaly. The very first liver function test (LFT) recorded in our system was at age 12 and demonstrated albumin 5.1 g/dL, total bilirubin (TB) 0.5 mg/dL, AST 36 IU/L, ALT 44 IU/L, alkaline phosphatase (ALP) 207 IU/L, and INR 1.2. Platelet count was 81,000/muL. As per the medical record, the liver biopsy performed at the outside institution at age 4 showed focal bridging fibrosis (slides not available for review).
In addition to the liver issue, his family was concerned about his developmental delay, e.g., started walking at age 2, spoke in several word phrases by age 2-3 years. At age 4, he developed a stutter, which significantly affected his expressive speech. Neurologic symptoms included significant tremors, motor disability, and peripheral neuropathy (e.g., foot drop requiring leg braces). Cavus foot was also noted. In childhood, he developed autistic behavior and attention deficits. A brain MRI at age 9 revealed mild cerebellar vermian atrophy.
Interestingly, one of the patient's sisters had very similar symptoms. No specific etiology was identified despite extensive work-up on both patients including molecular testing for Niemann-Pick C (NPC1 and NPC2), ATP8B1, BSEP, and ABCB11 (familial intrahepatic cholestasis); citrin; mitochondrial testing (electron transport chains) and BCSL1 gene; enzymatic testing including fatty acid oxidation, GM1 gangliosidosis, filipin, Niemann-Pick, gaucher, filipin, fructose 1, 6 bisphosphatase, and aldolase in the liver; biochemical testing including 24-hour urine copper, ceruloplasmin, acylcarnitine, and very-long-chain fatty acid panel; and mutations for cerebellar vermis hypoplasia-oligophrenia-ataxia-coloboma-hepatic fibrosis (COACH) syndrome including MKS3/TMEM67, CC2DA, and RPGRIP1L.
At the age of 14, whole exome sequence analysis revealed to harbor two variants in the SCYL1 gene, i.e., heterozygous for c.937delG (maternally inherited) and c.1509 1510delTG (paternally inherited) previously unreported. His mother was heterozygote for the c.937delG variant and did not harbor c.1509 1510delTG. His father was heterozygote for the c.1509 1510delTG variant and did not harbor the c.937delG variant. Both parents are asymptomatic. He was well and started a program at age 19 years for kids with intellectual disability for the goal to live independently. His last upper endoscopy was at age 12 with no significant findings. He has had regular abdominal ultrasound examinations that have been stable. His hemoglobin, albumin, and bilirubin at age 19 were within normal range.
At age 20, he developed jaundice again after fever and rhinorrhea. His LFT was notable for TB 7.7 mg/dL (DB 4.4), ALP 458 IU/L, ALT 692 IU/L, AST 304 IU/L, and INR 2.52. GGT was 20 U/L, consistent with low GGT cholestasis. Platelet count was 33,100/muL. There was no history of acetaminophen or salicylate use. Abdominal ultrasound showed cirrhotic morphology and splenomegaly. He did not respond to conservative management and underwent liver transplantation eventually. The explanted liver demonstrated 1,677 gram weighed green-colored (cholestatic) parenchyma with slightly nodular surface (Figure 1). Microscopic findings showed cirrhosis (Figure 1), cholestatic liver injury, and prominent bile ductular proliferation (Figure 2). Steatosis was minimal.
He recovered well but experienced postoperative biliary stricture requiring several occasions of endoscopic retrograde cholangiopancreatography with stent insertion. After 3 year follow-up, he has been stable with the stricture resolved. He is on tacrolimus and mycophenolate. No clinical suspicion of acute cellular rejection has been identified, nor has posttransplant liver biopsy ever been required. Most recent LFT showed TB 2.1 mg/dL (DB 0.4), ALP 72 IU/L, ALT 18 IU/L, AST 13 IU/L, and GGT 4 U/L. However, he still wears leg braces and has limited expressive language. Follow-up brain MRI also revealed persistent cerebellar atrophy.