Rare Hereditary Hemochromatosis

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

HFE, HAMP, TFR2, HJV, SLC40A1, SLC11A2, TNF, BMP6, CP, HP, BMP2, AKR1D1, B2M, HMOX1, ALAD, HLA-A, TFRC, HLA-H, CYBRD1, FTL, HLA-B, TMPRSS6, APOE, TF, UBE2D1, TIMP1, GNPAT, TLR4, ACO1, MMP2

HFE, HAMP, TFR2, HJV, SLC40A1, SLC11A2, TNF, BMP6, CP, HP, BMP2, AKR1D1, B2M, HMOX1, ALAD, HLA-A, TFRC, HLA-H, CYBRD1, FTL, HLA-B, TMPRSS6, APOE, TF, UBE2D1, TIMP1, GNPAT, TLR4, ACO1, MMP2, HEPH, FTH1, EPO, SUCNR1, COX8A, F5, PPP1R11, SOD2, SOD1, SHBG, ADIPOQ, TP53, UROD, ZKSCAN8, PCSK7, S100A9, GDF15, PIEZO1, TRIM31, NUP42, TNMD, SLC46A1, BTBD9, MCIDAS, LINC01194, CCL2, MDM2, UBL3, SERPINA1, GABPA, GAST, FXN, FOXC2, ELANE, CYLD, CTNNB1, CFTR, CELP, CD68, CALR, ARNTL, ALDH2, ALB, ALAS2, GAPDH, GNRH1, GPT, SMAD1, PGF, NMBR, NFE2L2, MPO, MMP3, SMAD7, IREB2, GSTP1, IL10, IL6, IGHG3, IGFALS, IFNG, HLA-F, MFT2

Drugs

(S)-3'-(OH)-desazadesferrithiocin-polyether, magnesium salt, 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, Deferasirox ( EXJADE, DEFERASIROX MYLAN )

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Rare hereditary hemochromatosis comprises the rare forms of hereditary hemochromatosis (HH), a group of diseases characterized by excessive tissue iron deposition. These rare forms are hemochromatosis type 2 (juvenile), type 3 (TFR2-related), and type 4 (ferroportin disease) (see these terms). Hemochromatosis type 1 (also called classic hemochromatosis; see this term) is not a rare disease.

Epidemiology

The rare forms of HH have a broad geographical distribution with few cases described.

Clinical description

Hemochromatosis causes chronic fatigue and bronzed skin pigmentation, with severe tissue damage in the liver, pancreas, joints, bone, endocrine glands, or heart, which results in various complications usually in adulthood including liver fibrosis (cirrhosis with the risk of hepatocellular carcinoma), diabetes mellitus, arthropathy, osteoporosis, hypogonadotropic hypogonadism, and cardiac failure.

Etiology

HH is due to several mutations in genes coding for proteins involved in the regulation of iron homeostasis. Hemochromatosis type 2 is due to HFE2 or HAMP gene (1q21, 19q13) mutations, type 3 to TFR2 (7q22) and type 4 to SLC40A1 (2q32) mutations.

Diagnostic methods

Diagnosis is based on biochemical testing using serum transferrin saturation and serum ferritin, and on magnetic resonance imaging (for diagnosing visceral iron overload). Molecular genetic blood testing allows the diagnosis to be established in a non-invasive way (i.e. without a liver biopsy). Biochemical abnormalities include elevated serum iron, transferrin saturation and ferritin. Ferroportin disease form A is generally asymptomatic and has uncommon biological features with high serum ferritin and normal or low transferrin saturation levels

Differential diagnosis

Differential diagnosis includes i) for hyperferritinemia: alcoholism, polymetabolic syndrome, and inflammatory conditions, ii) for visceral iron overload: post-transfusional iron overload in the case of hematological diseases such as thalassemia major, sickle cell disease, myelodysplastic syndromes, and rare anemias (see these terms).

Genetic counseling

Transmission is autosomal recessive for HH types 2 and 3 and autosomal dominant for HH type 4. Genetic counseling should be offered to affected families, informing them of the risk of inheriting the disease-causing mutation.

Management and treatment

Patients are treated by repeated phlebotomies that are usually initially performed on a weekly basis until iron excess has disappeared, after which they are performed every 1-3 months.

Prognosis

HH types 3 and 4 have a very good prognosis and patients have a normal life expectancy when treated early, before the development of severe visceral complications (especially cirrhosis). HH type 2 has a higher risk of mortality, particularly due to heart failure.