H63D: The Other Mutation (2021 version)

In 2010, the Iron Disorders Institute published the first seminal article on the underestimated risk of a homozygous HFE gene H63D mutation. This short but important article has lost none of its relevance. Since it is in danger of being forgotten and disappearing from more and more websites, we are publishing a reprint of the still seminal article, expanded with some new findings.

Incidence of a clinically relevant H63D syndrome in carriers of a homozygous mutation of HFE gene H63D

H63D syndrome is a phenotype of a homozygous mutation of the HFE gene H63D, which is otherwise known to cause at most mild classical hemochromatosis. H63D syndrome leads to an iron overload in the body (especially in the brain, heart, liver, skin and male gonads) in the form of non-transferrin bound iron (NTBI) poisoning. Hallmark symptoms and causal factor for H63D syndrome is a mild hypotransferrinemia with transferrin saturation values >50%. H63D syndrome is an incurable multi-organ disease, leading to permanent disability. Our objective was to find out how many carriers of a homozygous H63D mutation develop H63D syndrome. For this purpose, we systematically evaluated the medical records of homozygous carriers of the mutation. We found the syndrome in about 10% of patients with a homozygous mutation. Since a homozygous mutation on the HFE gene H63D is relatively common, the results of our study suggest many undetected or misdiagnosed cases.

Hemochromatosis Arthropathy in Heterozygous HFE H63D Mutation Without Iron Overload- An Entity Less Commonly Touched

Human homeostatic iron regulator protein gene (HFE gene) H63D mutations even when homozygous are rarely associated with iron overload. These mutations, independent of iron status, are associated with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) leading to arthropathy even for heterozygotes. The arthropathy does not respond to iron depletion. We report a case of a 62-year-old male with chronic generalized arthralgias with no evidence of iron overload or elevated inflammatory markers with characteristic radiographic hook-like osteophytes suggestive of hemochromatosis arthropathy. Further, he was found to be a carrier of HFE H63D mutation. Recognition of the association can help guide goal directed management.

Metastatic breast cancer presenting as acute liver injury: diagnostic dilemma in the setting of suspected hemochromatosis

A 70-year-old female with a history of lobular carcinoma of the breast, status post-mastectomy followed by adjuvant radio-chemotherapy in remission for 4 years was admitted with the features of acute liver failure (ALF). Iron studies revealed a hemochromatosis picture and the CT and MRI scans of the abdomen suggested cirrhosis. An extensive workup failed to identify an etiology. A trans-jugular liver biopsy was obtained and revealed poorly differentiated carcinoma consistent with the metastasis of breast primary. The patient’s condition deteriorated and died within a week following the onset of acute hepatic failure. DNA testing revealed that the patient was heterozygous for H63D mutation. In cases of ALF with the suspicion of malignancy, liver biopsy should be obtained to evaluate an infiltrative hepatic disease.

IDENTIFIKASI MUTASI H63D GEN HFE PADA KELAINAN HBE

The H63D HFE mutation has been reported to be responsible for primary haemochromatosis. The allele frequency in Indonesianpopulation is about 2.8%. Co inheritance between H63D mutation and hemoglobin disorders such as Thalassemia may increase theseverity of iron overload. Nevertheless, the coinheritance of this mutation with HbE disorder is the most common hemoglobin disorderin Indonesia and the gene frequency have not been reported especially in Javanese ethnic. To identify the presence and the frequency ofH63D HFE mutation in HbE disorder among Javanese ethnic. A cross sectional study involved 24 Javanese individuals who consist of21 HbE heterozygotes (HbAE) and 3 HbE homozygotes (HbEE) subjects. The subjects were screened for H63D mutation by digestion ofPCR products with MbO I restriction endonuclease. The genotype frequency for wt/wt was 95.24% in HbAE, 100% in HbEE and for wt/H63D was 4.76% in HbAE. The allele frequency for H63D HFE mutation was 2.08% in total sample of HbE. The allele frequencies inHbAE and HbEE individual were 2.38% and 0%, respectively. H63D HFE mutation is found in 24 Javanese ethnic individual with HbEdisorder. However, the allele frequency of H63D HFE mutation is low and almost similar to the allele frequency of H63D HFE mutationin Indonesian population.

HFE GENE MUTATIONS

Objectives: To determine the frequency of two common HFE Gene Mutations(C282Y & H63D) in an immigrant population (British Pakistanis) in UK. Study Design: Crosssectional study. Setting: University of Lincoln UK. Duration: Duration of study was 12 monthsfrom 01/09/2012 to 31/08/2013. Material and Methods: Two hundred immigrant Pakistani (BP)chromosomes (100 samples; 50 male and 50 female) from major cities of UK and 200 ancestralorigin Pakistani chromosomes (100 samples; 50 male and 50 female) were analysed by PCRRFLPfor the presence of the H63D and C282Y mutations. Results: Eight individuals were foundto be heterozygous for the H63D mutation and one individual was found to be homozygousfor the H63D mutation, therefore, the H63D mutation was observed to have a frequency of 8%in immigrant Pakistani (BP) population sample and similar results were observed in ancestralorigin population from Pakistan. The C282Y mutation was not detected at all. Conclusion: Wefound that our results are close to Saudi-Arabian and Indian population (8.5% & 9.1% H63Dmutation, respectively) and in accordance with the global spread of the H63D mutation.

Clinical significance of HFE gene mutations in patients with refractory anemia with ring sideroblasts (RARS).

e18556 Background: RARS is a subtype of myelodysplastic syndromes (MDS) defined by < 5% blasts and ≥15% ring sideroblasts (WHO 2008). Hereditary hemochromatosis is a disorder characterized by dysregulations in iron absorption, largely associated with C282Y and H63D mutations of the HFE gene. Iron levels are elevated in both disorders and pathophysiologic correlations were suggested. HFE gene mutations were previously found higher in MDS compared to controls (50% vs 36%) ( Nearman et al, Am J Hematol 2007). Methods: A total of 168 RARS patients’ data from 1994 to 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our center. We searched patients’ records retrospectively to Identify those tested for HFE gene (C282Y, H62D, S65C) mutations, done inside or outside our institution. Survival estimates were calculated using Kaplan-Meier curves. Results: Out of the 168 RARS patients, only 17 (10%) were tested for HFE gene mutations. Out of the 17 tested, 11 (65%) were found to have mutations; 2 of which (18%) had homozygous H63D mutation, 1 patient (9%) had double heterozygous H63D and C282Y mutations, 5 (45%) had only one H36D heterozygous mutation vs 3 patients (27%) with only one C282Y heterozygous mutation. Only one patient was tested for the additional S65C mutation and it was not detected. H63D mutation was present in a total of 8 patients (73%) vs C282Y mutation which was present in 4 patients (36%). Bone marrow iron stores were increased in all 17 tested patients, except one who had decreased stores, this patient had one heterozygous C282Y mutation. Median overall survival (mOS) was 117 months in the HFE mutated patients vs 75 months in the non-mutated (p = 0.6). Conclusions: Our study found the HFE gene, when tested, to be mutated in higher frequencies among patients with RARS compared to that reported in the general population (65% vs 36%), with H63D mutation in almost three quarters of all mutated patients. Although it did not reach statistical significance, the longer survival observed among HFE mutated patients compared to the wild-type raises the question whether testing for HFE gene mutations among patients with MDS-RARS should be further explored.