Haemochromatosis revisited

Table 2 Previous classification of haemochromatosis

Haemochromatosis types	Gene	Location	Inheritance	Gene product function	Main clinical manifestations
1	HFE	6p21.3	AR	Involved in hepcidin synthesis via BMP6, interaction with TFR1.	Iron overload and known manifestation of classical haemochromatosis (HFE type). Arthropathy, skin hyperpigmentation, liver damage, diabetes, endocrine dysfunction, cardiomyopathy, hypogonadism.
2A	HJV	1p21	AR	Involved in hepcidin synthesis, BMP co-receptor.	Type 2: earlier onset, < 30 yr. Severe iron overload and juvenile form of haemochromatosis.
2B	HAMP	19q13	AR	Hepcidin, produced mainly in hepatocytes, downregulates iron efflux from enterocytes via ferroportin.	Hypogonadism and cardiomyopathy more prevalent. Severe iron overload and juvenile form of haemochromatosis.
3	TFR2	7q22	AR	Transferrin receptor 2, mediates cellular uptake of transferrin-bound iron and is involved in hepcidin synthesis.	Phenotypes can range from moderate to severe form of haemochromatosis.
4A	SLC40A1	2q32	AD	Ferroportin is an iron exporter in duodenal.	Lower tolerance to phlebotomies with risk of anaemia. The phenotype strongly differs from newly defined haemochromatosis (mild clinical symptoms, major spleen iron overload, major hyperferritinemia without transferrin saturation increase).
4B	SLC40A1		AD	Ferroportin acting a hepcidin receptor.	Very rare; in general, clinically similar to HFE-haemochromatosis.

TFR2: Transferrin receptor 2; HFE: Encodes HFE protein; HJV: Encodes hemojuvelin; HAMP: Encodes hepcidin; TFR2: Encodes transferrin receptor 2; SLC40A1: Encodes ferroportin; BMP6: Bone morphogenetic protein 6, AR: Autosomal recessive; AD: Autosomal dominant.