S5429 Cirrhosis Secondary to Hereditary Hemochromatosis in a Young Man With Williams Syndrome

Introduction: Williams syndrome (WS) is a rare microdeletion disorder with loss of a region of chromosome 7 that results in multisystem manifestations. We are presenting a case of a patient with WS and hereditary hemochromatosis (HH). To our knowledge, an association between WS and hemochromatosis has never been made. Case Description/Methods: A 27-year-old man with history of WS was initially referred to hematology for leukopenia, macrocytosis, thrombocytopenia, progressive splenomegaly, and axillary lymphadenopathy. Workup revealed elevated liver chemistries in a hepatocellular pattern, and cross-sectional imaging findings of retroperitoneal varies with no radiographic suggestion of cirrhosis. Given concern for portal hypertension, he was evaluated by Gastroenterology. Extensive workup revealed iron studies consistent with hemochromatosis, with HFE testing reveling C282Y homozygosity, consistent with HH. He started weekly phlebotomy, and ferritin decreased from 1180 to the 200s within months. He was later diagnosed with type 2 diabetes and started on treatment for glycemic control and presumed exocrine pancreatic insufficiency. The patient eventually developed ascites with persistent liver chemistry elevation. He underwent liver biopsy which was consistent with diagnosis of HH and cirrhosis. His course was further complicated by severe hepatic encephalopathy. He is now undergoing liver transplant evaluation. Discussion: This patient has the most common HFE mutation in type 1 HH. However, his course has been far from common. Whereas HH typically presents in men around the fifth decade of life, this patient was diagnosed with diabetes and progressed to end stage liver disease by his early thirties despite early initiation of phlebotomy treatment. The proposed metabolic complications of WS, which include loss of genes that ordinarily regulate insulin secretion and glucose regulation, are suspected to interact with the consequences of iron overload in this patient in previously unidentified ways.1 The underlying metabolic abnormalities in WS may represent a risk factor for development of Metabolic Dysfunction-Associated Steatotic Disease (MASLD), essentially acting as a double hit to pre-dispose to development of advanced liver disease in this patient with HH. More research is needed to further characterize WS as a potential independent risk factor for liver disease. Reference 1. Stanley TL, Leon A, Pober BR. Growth, body composition, and endocrine issues in Williams syndrome. Curr Opin Endocrinol Diabetes Obes. 2021;28(1):64-74.