Cholestasis in Siblings: A Rare Case of Progressive Familial Intrahepatic Cholestasis: An Abstract from Akron Children’s Hospital Resident and Fellow Academic Day

A 4-week-old female presents to the emergency department for concerns of jaundice with a significant family history of onset of liver failure in her older sister, requiring liver transplantation at 2 years of age, who presented similarly when she was born. Apart from the jaundice, she was feeding, stooling, and behaving appropriately. Her physical exam was remarkable for scleral icterus, jaundice extending from her head to her abdomen, and a small umbilical hernia. She had a conjugated hyperbilirubinemia with direct bilirubin of 8.4 on admission. Initial workup consisted of RUQ ultrasound, which showed a decompressed gallbladder and a normal-sized liver without any obstructive process. Labs revealed alpha 1-antitrypsin is abnormal but not at a level of deficiency. Coagulation studies along with albumin were normal, suggesting normal synthetic liver function. Her metabolic workup showed non-specific elevations in plasma amino acid levels with elevated threonine, a-amino-N-butyric acid, cystine, ornithine, lysine, and carnosine. Urine bile acids did not show any defect in the biosynthetic pathway or beta oxidation. She had normal organic acids, lactate, and pyruvate levels. An intraoperative cholangiogram was attempted but was unable to be completed due to the gallbladder being collapsed. Liver biopsy revealed hepatic parenchyma with intracanalicular cholestasis without evidence of bile duct plugging, ductular proliferation, or portal fibrosis, findings which argue against biliary atresia. Liver biopsy was not consistent with Alpha 1-antitrypsin, with a lack of enlarged PAS-positive periportal globules. MMP-7 was mildly elevated; however, not to the level of biliary atresia. Rapid whole-genome sequencing found a homozygous PSKH1 mutation. After testing her sister, who required a liver transplant, she was also positive for the PSKH1 mutation. Reports of PSKH1 mutations have been associated with hepatorenal ciliopathy, such as liver and renal anomalies, hepatic and/or biliary cirrhosis with cholestasis. PFIC is a group of disorders that encompasses defects in bile acid secretion and transport that are often associated with growth failure and progressive liver disease. Our case highlights a rare subtype of PFIC13, a specific disorder that is associated with the mutation of PSKH1. This gene encodes a protein serine kinase H1, which plays a role in intracellular trafficking and cystogenesis. The defect in this gene can lead to dysfunctional cilia, which can cause early-onset progressive liver dysfunction with intrahepatic and biliary cholestasis that may lead to cirrhosis and the possible need for liver transplantation. A unique aspect of PSKH1 is its association with renal involvement. It can be associated with unilateral renal agenesis and glomerulosclerosis, neither of which this patient does not demonstrate. This case showcases a rare presentation of PSKH-1-related progressive familial intrahepatic cholestasis as a cause for early-onset cholestatic liver disease and highlights the early consideration of genetic cholestatic testing in infants with unexplained cholestasis.