Genetic studies by NGS Panels
Panel for Hereditary Hemochromatosis and Hyper- / Hypoferritinemia (Code 10010)

Hereditary hemochromatosis (HH) is a group of genetic diseases characterized by excessive accumulation of iron in tissues. There are 5 types of HH: HH type 1 (HFE), HH type 2 (HJV and HAMP genes), HH type 3 (TFR2 gene), HH-4 (gene SLC40A1) and HH due to mutations in gene BMP6. Forms 1, 2 and 3 are autosomal recessive diseases and form 4 and due to mutations in BMP6 gene are dominant.

Hereditary hemochromatosis (HH) Type 1, also called classic hemochromatosis (OMIM # 235200) is the most common form of HH and is mainly due to Cys282Tyr homozygous mutation of the HFE gene. This type of HH affects men more than women. From a clinical standpoint, the disease begins between 30 and 50 years of age. Hemochromatosis type 1 causes chronic fatigue, dark pigmentation of the skin and can severely affect the liver, pancreas, joints, bones, endocrine glands, or heart, resulting in various complications that appear in adulthood, such as hepatic fibrosis (cirrhosis with hepatocellular carcinoma risk), diabetes mellitus, arthropathy, osteoporosis, hypogonadotropic hypogonadism and heart failure. Biochemical abnormalities include elevated serum iron, serum transferrin saturation and serum ferritin levels. The molecular genetic blood test, showing a homozygous Cys282Tyr, confirm the diagnosis of HH in a non invasive way. Treatment consists of phlebotomy (blood draws), initially these are made weekly, generally reducing in frequency. Hemochromatosis type 1 has a very good prognosis if diagnosed early and treated appropriately before the development of serious complications.

Juvenile hemochromatosis, or HH type 2a (OMIM # 602390) was first described in 1930 under the name of «hepatorenal heart and endocrine syndrome» and is due to the mutation in the HJV gene (alternative name HFE2) that codes for the hemojuvenil protein (HJV). Hemochromatosis type 2b, also called juvenile HH (OMIM # 602390) is a rare form of HH associated to mutations in the hepcidin gene (HAMP). This rare disease is characterized by a elevation of serum ferritin levels (hyperferritinemia), transferrin saturation and serum iron, which generate a severe iron overload, cardiac failure, and hypogonadotropic hypogonadism in young age (adults under 30 years).

Hemochromatosis type 3 (TFR2 gene) is a rare disorder (OMIM # 604250) characterized by elevated serum ferritin levels (hyperferritinemia), transferrin saturation and serum iron, which generated a severe iron overload in several tissues, especially in liver. The clinical manifestations of HH type 3 are very
similar to the HH type 1 (see above), but these patients usually have more severe symptoms and at younger ages than in the case of HH type 1.

Mutations in the SLC40A1 gene coding for ferroportin (FPN1) (OMIM # 604653) causes two types of disorders of iron metabolism both autosomal dominant (OMIM # 606069):

Ferroportin disease 4a is the most common and usually is asymptomatic without any complications or hepatic iron overload in the future. This disease is characterized by elevated serum ferritin but normal values and / or low transferrin saturation and a tendency to anemia in patients who have been given phlebotomy. Iron overload occurs in macrophages of the reticuloendothelial system of the spleen and liver, but not in hepatocytes. The course of this disease is rather benign nature.

Ferroportin disease 4b presents elevated serum ferritin and transferrin saturation and hepatic iron overload in hepatocytes can lead to hepatomegaly and cirrhosis. This type of ferroportin disease is less common than the 4a and is due to specific mutations that confer resistance to ferroportin to be degraded by interaction with the hormone hepcidin.



Ferritin is the protein responsible for the storage and intracellular distribution of iron. It consists of two subunits called L-ferritin and H-ferritinL. The synthesis of these subunits is controlled by regulatory proteins called Iron-regulatory proteins (IRPs) that bind to a regulatory element called iron-responsive element (IRE) present in the 5’UTR of mRNA of each of these two subunits.

In 1995 the Hereditary Hyperferritinemia Cataract Syndrome (HHCS) (OMIM # 600886) was first described. It is characterized by elevated levels of serum ferritin without iron overload, congenital cataracts and autosomal dominant inheritance. Excessive production of ferritin is due to mutations in the regulatory element called Iron-responsive element (IRE) light chain gene-ferritin L (FTL). Ferritin excess accumulates in the lens which leads to the development of cataracts. The degree of affectation varies even between individuals with the same mutation. A correct genetic diagnosis of this disease is important, as it is often confused with hereditary hemochromatosis due to the high levels of serum ferritin present in both diseases.

The overproduction of serum ferritin may also be due to mutations in the coding sequence of the gene for L-ferritin. In 2009 Kannengiesser and colleagues described a new form of genetic hyperferritinemia, known as benign hyperferritinemia without iron overload, with dominant inheritance (Kannengiesser C, et al. Haematologica. 2009).

In 2001, Kato and colleagues described a mutation of the regulatory element IRE (iron-responsive element) located in the 5 ‘UTR of the gene for ferritin-H (fth1) in a Japanese family with an iron overload syndrome and pattern of dominant inheritance (Kato et al. Am. J. Hum. Genet. 69:191-197, 2001) (OMIM # 134770). According to this study, this mutation produces iron overload in liver, pancreas and heart, and elevated serum iron and ferritin.



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