Underdiagnosis of hereditary haemochromatosis: lack of presentation or penetration?

Background: The majority of hereditary haemochromatosis (HH) patients are homozygous for the C282Y mutation in the HFE gene. We have demonstrated a homozygote frequency of 1 in 83 for the C282Y mutation in a retrospective analysis of Irish neonates. However, a fully developed phenotype is not observed at the same frequency clinically, suggesting that a large proportion of Irish HH patients may remain undiagnosed.

Aims: To determine whether underdiagnosis of HH results from the non-specific nature of early symptoms or incomplete penetrance of the C282Y mutation.

Methods: Seventy nine C282Y homozygous individuals identified from family screening for HH and 30 HH probands were investigated. Non-specific symptoms (fatigue, arthropathy, and impotence) and their association with iron indices (transferrin saturation and serum ferritin) and hepatic iron deposition were analysed.

Results: We found that 78% of men (mean age 42 years) and 36% of women (mean age 39 years) who were identified as C282Y homozygotes following family screening had iron overload, as defined by a transferrin saturation >or=52% combined with a serum ferritin >or=300 microg/l for men and >or=200 microg/l for women. The frequency of reports of non-specific symptoms in those individuals with iron overload was not significantly different from those who did not have iron overload.

Conclusions: Our findings indicate that underdiagnosis of HH may be due to the non-specific nature of early symptoms and less frequently to the incomplete penetrance of the C282Y mutation.