Case for C1: Genetic Mechanisms
A 50 year old Caucasian male physician is concerned that he may be at risk for
developing hemochromatosis and wants you to interpret his bloodwork. His medical
history is unremarkable with the exception of hypercholesterolemia, for which he takes a
statin. His family history is remarkable for his father presenting at age 60 with bronzed
skin and diabetes, found to have iron overload and subsequently underwent therapeutic
phlebotomies. Both father’s diagnostic bloodwork and son’s studies are listed below:
Father – age 70
Son – age 50
Normal Range
Serum iron
232
106
65-170 mcg/dL
Transferrin
284
230
200-400 mg/dL
Total iron binding
capacity
355
288
250-450 mg/dL
% Saturation
65
37
20-55%
Ferritin
1518
217
10-300 ng/mL
HFE genotype C282Y
Homozygous
Heterozygous
1) Interpret the father’s and the son’s iron studies.
The father has elevated serum iron associated with increased transferrin saturation,
and an elevated ferritin indicative of both increased iron absorption and iron storage.
The son has normal iron studies.
2) Do the son’s iron studies support the diagnosis of hemachromatosis?
No. He does not have evidence of either increased absorption or increased iron
stores. Additionally he is only a carrier of the HFE mutation, making it highly unlikely
that he has a genetic predisposition to iron overload.
3) Which of these studies is the best measure of long term iron storage?
Ferritin.
4) Which of these studies is the best assessment of daily iron absorption?
Serum iron and transferrin saturation.
Another family member has iron studies which are reported as follows:
FATHER – age 70
SON – age 46
NORMAL RANGE
Serum iron
232
176
65-170 mcg/dL
Transferrin
284
230
200-400 mg/dL
Total iron binding
capacity
% saturation
355
266
250-450 mg/dL
65
65
20-55%
Ferritin
1518
611
10-300 ng/mL
HFE genotype
C282Y
Homozygous
Homozygous
5) Does this son have iron overload?
Yes, he has evidence of iron overload.
6) Why is his ferritin so much lower than his father’s?
He is younger than his father was at the time of his iron studies, and the degree of
iron overload is a function of time.
7) Which genes can cause hemochromatosis when mutated? Describe the
inheritance patterns seen.
In this case, and in classic (Type 1) hemochromatosis in general: 6p21.3, autosomal
recessive inheritance. This mutation accounts for >80% of hemochromatosis cases.
Other mutations in HFE1 (H63D) have also been reported. 4 additional iron overload
disorders labeled hemochromatosis have been identified:
- Juvenile hemochromatosis (HFE2) autosomal recessive, hemojuvelin(HJV) gene
on chr 1q21 (HFE2A) and hepcidin(HAMP) gene on chr 19q13 (HFE2B)
- HFE3- autosomal recessive, mutation in Transferrin receptor 2(TFR2) gene on
chr 7q22
- HFE4- autosomal dominant, caused by mutation in SLC40A1 gene on chr 2q32
8) Should other family members be tested? What type of molecular genetic
testing could be done?
Taking the brother’s and father’s genotypes together, (and assuming the brothers
have the same father!) mother must be a carrier, and other children have a 50%
chance of being homozygotes also. Homozygotes do have an increased risk of
significant iron overload, although the probability of iron overload is not 100% in HFE
C282Y homozygotes in the population at large. There are significant modifiers of
iron absorption beyond the HFE gene. In this family however, there are affected
homozygotes, indicating an increased risk for iron overload for homozygotes.
Because we know the mutation in this case, targeted mutation analysis for
HFEC282Y is the only analysis needed. If you were working up a new patient with
hemochromatosis, it would be appropriate to do targeted analysis for this and the
second most common (H63D) mutation, and if these were negative to use sequence
analysis to identify other less common mutant alleles associated with HFE.
9) What are modifiers of iron overload?
Age, gender, diet, polymorphisms of other genes controlling iron absorption