The Southern French Registry of Genetic Hemochromatosis, a Tool for Determination of Clinical Prevalence and Genotype Penetrance of the Disorder.
Authors: Aguilar-Martinez Patricia , Bismuth Michael , Blanc Francois , Blanc Pierre , Cunat Severine , Dereure Olivier , Dujols Pierre , Giansily-Blaizot Muriel , Jorgensen Christian , Konate Amadou , Larrey Dominique , Le Quellec Alain , Mura Thibault , Raingeard Isabelle , Ramos Jeanne , Renard Eric , Rousseau Florence , Schved Jean-Francois , Picot Marie Christine 
Published: October 2019

Abstract 4055

Poster Board III-990

Background

Hereditary hemochromatosis (HH) is a monogenic disorder, mainly due to the HFE C282Y homozygous mutation. This genotype is very widespread, with a prevalence of nearly 1 out of 200, among individuals of North European descent. However, despite great progress in our knowledge during the last decade, there are still debates about the true clinical prevalence and about the penetrance of the disorder, with penetrance estimates ranging from 50-60% to less than 1% depending on the adopted definition of penetrance.

Design and methods

A registry of patients with HH (systematic record of patients with HH in a defined administrative area) was implemented in South France and a regional health network was developed to allow including all the diagnosed patients living in the area. C282Y homozygous patients were classified into stages according to the French National Authority for Health (HAS) (Brissot P, de Bels F. Hematology Am Soc Hematol Educ Program 2006:36-41). Patients stage 2 (biological iron overload), 3 and 4 (clinical stages, stage 4 including the most severely affected patients with live threatening conditions with impact on survival, such as diabetes, chronic liver disease, cirrhosis or cardiopathy) were included in the registry during a 6 year- period. A yearly follow-up was performed in order to update the registry (particularly removal of patients either deceased or who migrated from the region). Frequency of the C282Y genotypes in this region (homozygotes: 15.7 per 10,000) was known from previous studies, allowing to calculated the penetrance of the different stages.

Results

A total of 352 symptomatic C282Y homozygotes were identified, resulting in a prevalence of 1.83 per 10,000 subjects over 20 years [CI95%: 1.63-2.02]. The total calculated penetrance was 11.6%, slightly higher in males (13.8%) than in females (9.7%). A markedly lower penetrance at 5.3% was found in patients under 40, and a maximum at 22.9% in patients aged 50-54. Among 249 patients with full record, the majority (58%) was stage 3, 24% stage 2 and 18% stage 4. The penetrance was 2.8%, 7.0% and 2.2% for stages 2, 3 and 4 respectively. There was a higher proportion of males and excessive alcohol intake was more frequent in stage 4 than stage 2 and 3 combined.

Conclusions

A regional genetic hemochromatosis registry with strict design and inclusion criteria is a useful tool for characterizing the disease history and the prevalence of the clinical manifestations using the proposed HAS classification into stages. The total penetrance of the C282Y homozygous genotype for the three stages with either biological or clinical iron overload was around 12%. Overall, the clinical penetrance (stage 3 and 4) was 9.2%, whereas the penetrance of the most severe manifestations (stage 4) was low, at only 2.2%, with a predominance of men. These results strengthen the need for new biological markers which can help define prognostic criteria in C282Y homozygous subjects diagnosed at an early stage.

Disclosures:

No relevant conflicts of interest to declare.