| Hemochromatosis type 1 (HFE-related hemochromatosis) |
| • Epidemiology: prevalence varies according to descent showing typical north-to-south decreasing gradient; age of presentation: 40–60 years |
| • Genetics: autosomal recessive; p.Cys282Tyr is the most frequent mutation; p.His63Asp is a common variant; rare mutations are reported. p.Cys282Tyr homozygotes have high biochemical penetrance and low clinical penetrance and variable expression; p.Cys282Tyr/p.His63Asp compound heterozygotes and p.H63D homozygotes have low biochemical penetrance (high TSAT and ferritin in 9% and 5%, respectively) and very low clinical penetrance |
| • Clinical presentation: frequently asymptomatic or with mild and non-specific manifestations (fatigue, arthralgias, hepatomegaly, mild hypertransaminasemia). Organ damage is less frequent and develop in 25–60% of male patients and likely less than 5% of women in different series, most commonly: liver fibrosis/cirrhosis, diabetes, arthropathy; less frequently, cardiopathy and hypogonadism. Hepatocarcinoma is the prevalent cause of death in cirrhotics |
| • Biochemical presentation: variably increased TSAT and serum ferritin |
| Hemochromatosis type 2A and 2B (HFE2-, HAMP-related hemochromatosis) |
| • Epidemiology: very rare (about 90% HFE2-related) with no ethnic background; no gender prevalence; age of presentation: 10–30 years, but few cases showed later presentation |
| • Genetics: autosomal recessive; fully penetrant, severe expression; p.G320V is the most common mutation in HFE2-related hemochromatosis while other mutations are often private |
| • Clinical can be asymptomatic or with mild and non-specific signs and symptoms in children; severe manifestations in variable combination (hypogonadism, cardiopathy, diabetes, cirrhosis) around twenties. Cardiopathy the prevalent cause of death in untreated patients |
| • Biochemical presentation: very high TSAT (often >70%) already present in children, early and marked increases of serum ferritin in the mid-teens |
| Hemochromatosis type 3 (TFR2-related hemochromatosis) |
| • Epidemiology: very rare; no ethnic background; gender prevalence uncertain; age of presentation: 20–50 years |
| • Genetics: autosomal recessive; often private mutations; high penetrance, variable expression |
| • Clinical presentation: can be asymptomatic or with mild non-specific signs and symptoms in early stages. Liver cirrhosis, diabetes and hypogonadism, and less frequently, cardiomyopathy occur in young adults and adults |
| • Biochemical presentation: very high TSAT (often >70%) already present in children, and serum ferritin markedly increased in young adulthood |
| Hemochromatosis type 4 (SLC40A1-related hemochromatosis, once hemochromatosis type 4A) |
| • Epidemiology: very rare; no ethnic background; milder expression in females; age of presentation: 20–60 years |
| • Genetics: autosomal dominant; incomplete penetrance and variable expression at biochemical and clinical level |
| • Clinical presentation: similar to hemochromatosis type-1 |
| • Biochemical presentation: variably increased TSAT and serum ferritin |
| Atransferrinemia |
| • Epidemiology: ultra-rare, less than 15 cases in the world; no ethnic background; no gender prevalence; age of presentation: 1–2 years |
| • Genetics: autosomal recessive; private mutations |
| • Clinical presentation: severe microcytic anemia that may require blood transfusion. If untreated, growth defect and severe iron-related complications and death may occur. Survival depends on replacement therapy |
| • Biochemical presentation: severe microcytic anemia, very low serum iron, undetectable serum transferrin level; variably increased serum ferritin |
| DMT1 deficiency |
| • Epidemiology: ultra-rare, less than 10 cases in the world: no ethnic background; no gender prevalence; age of presentation: post-natal to young adult |
| • Genetics: autosomal recessive; private mutations |
| • Clinical presentation: severe microcytic anemia that may require blood transfusion. If untreated, growth defect may occur. Liver iron overload can be severe even in non-transfused patients |
| • Biochemical presentation: severe microcytic anemia, high serum iron and TSAT; variably increased serum ferritin that are disproportionally low compared to liver iron concentration |
| Ferroportin disease (formerly hemochromatosis type 4A) |
| • Epidemiology: rare; no ethnic background; no gender prevalence; age of presentation: 20–60 years |
| • Genetics: autosomal dominant; incomplete penetrance and variable expression at both biochemical and clinical level |
| • Clinical presentation: frequently asymptomatic; frequently asymptomatic; no definite conclusions regarding pathogenic link between iron accumulation and liver damage, a single report described progression to liver fibrosis |
| • Biochemical presentation: variably increased serum ferritin with normal TSAT. In later stages increased TSAT may occur |
| Aceruloplasminemia |
| • Epidemiology: very rare; no ethnic background; no gender prevalence; age of presentation: 20–60 years |
| • Genetics: autosomal recessive; variable expression; mutations are often private |
| • Clinical presentation: diabetes, microcytic anemia, retinal degeneration, a wide spectrum of neuropsychiatric symptoms. Diabetes and anemia may precede neurological manifestations even by decades |
