PF501 HOMOZYGOUS I281T MUTATION IN HJV CAUSING INDOLENT JUVENILE HEMOCHROMATOSIS WITH A MIDDLE TO LATE ONSET
Authors: Takami A. , Tatsumi Y. , Sakai K. , Toki Y. , Ikuta K. , Kato K. , Takami K. 
Published: December 2023

Background:Juvenile hemochromatosis (JH; hemochromatosis type 2A) is a rare autosomal recessive disorder of systemic iron overload due to homozygous mutations of HJV (HFE2) which encodes hemojuvelin, an essential regulator of hepcidin expression, leading to intestinal iron hyperabsorption because of hepcidin deficiency. JH usually occurs younger than 30 years old, and causes liver fibrosis, hepatocellular carcinoma, diabetes, hypogonadism and heart failure with fatal outcomes.Aims:Here we report two Japanese siblings with JH caused by a homozygous I281T mutation in HJV, who unusually showed an indolent clinical course with a middle to late onset.Methods:After obtaining a written informed consent from each individual, blood samples were collected, followed by genomic DNA purification, and the coding regions of HFE, HFE2 (HJV), HAMP, TFR2, and SLC40A1 were sequenced. Genetic mutation was then evaluated by comparing the sequencing results to open access genetic information on the NCBI websites.Results:Patient #1 is a 38‐year‐old woman, who was referred to us due to 1‐year history of amenorrhea, thirst and weight loss. The patient's laboratory findings showed high levels of transferrin saturation (93%) and serum ferritin (2274 ng/mL), insulin‐dependent diabetes, iron deposition of the anterior pituitary gland by nuclear magnetic resonance (NMR) with hypogonadism, and massive iron deposition in hepatocytes by liver biopsy. Phlebotomy effectively improved iron overload as a treatment of hemochromatosis and has been continued for more than 15 years on an outpatient basis. Patient #2, aged 55, is an elder sister of the patient #1, who referred to us because due to liver dysfunction, dyslipidemia and hyperglycemia for 3 years and thirst for 1 year. She was also found to have high levels of transferrin saturation (92%) and serum ferritin (4340 ng/mL), insulin‐dependent diabetes, iron deposition of the pituitary gland by NMR with hypogonadism, massive iron deposition in hepatocytes by liver biopsy, and cardiomyopathy with congestive heart failure. Phlebotomy successfully improved organ damages associated with iron overload and has been continued for more than 4 years on an outpatient basis. It was later found that serum levels of hepcidin were below the measurement sensitivity in both patients.To identify the causative genetic defect responsible for the iron overload in these two siblings (probands), we screened them for mutations in the genes involved in hereditary hemochromatosis as well as their healthy brother, and two healthy sons of the patient #1. Both probands were homozygous for a missense mutation in HJV exon 4 (842 T>C; I281T). Both of the patient #1's sons were heterozygous for I281T of HJV, and the brother had no mutations related with hemochromatosis.Summary/Conclusion:We have reported two Japanese siblings (onset, 37 and 52 years) with the homozygous mutation of HJV I281T in middle to late onset with an indolent clinical course. HJV mutations, which are the cause of JH, have been widely identified mainly in a Caucasian population. However, the homozygous mutation of HJV I281T as observed in the current study has only been identified in one Greek patient (Papanikolaou G. Nature genet. 2004), whose JH notably occurred at the age of 39 years and was diagnosed at the age of 49 years. Therefore, together with the current findings, it was suggested that the homozygous mutation of I281T may be associated with an indolent clinical course and a middle to late onset of JH.