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Juvenile Hereditary Hemochromatosis

Synonym: Hemochromatosis, Type 2. Includes: HAMP-Related Juvenile Hemochromatosis, HJV-Related Juvenile Hemochromatosis
, MB ChB, PhD, FRCPC
Vice President, Clinical
Xenon Pharmaceuticals Inc
Burnaby, British Columbia, Canada

Initial Posting: ; Last Update: August 11, 2011.

Summary

Disease characteristics. Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has not been reported. The main cause of death is cardiac disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.

Diagnosis/testing. Serum ferritin concentration ranges from 1000 to 7000 µg/L. Transferrin-iron saturation is typically very high, often reaching 100%. MRI is used as a noninvasive method of quantifying hepatic iron overload. A hepatic iron index of higher than 1.9 on liver biopsy suggests iron overload. The two genes in which mutations are known to cause juvenile hemochromatosis are HJV (HFE2) (locus name HFE2A) encoding hemojuvelin, accounting for more than 90% of cases, and HAMP (HEPC) (locus name HFE2B) encoding hepcidin, accounting for fewer than 10% of cases.

Management. Treatment of manifestations: Phlebotomy for treatment of iron overload is the same as for classic HFE-associated hemochromatosis, i.e., phlebotomy of one unit of blood (~200 mg of iron) one to two times per week for up to two to three years to reduce iron stores to desired levels (serum ferritin concentration below 50 ng/mL and normal transferrin-iron saturation), followed by phlebotomies to maintain normal serum iron studies. Conventional treatment of secondary complications, including hypogonadotropic hypogonadism, arthropathy, cardiac failure, liver disease, diabetes mellitus.

Prevention of primary manifestations: Regular phlebotomies until excess iron stores are depleted.

Prevention of secondary complications: Hormone replacement therapy (HRT) to prevent osteoporosis.

Surveillance: Monitor those at risk with annual measurement of serum ferritin concentration and transferrin-iron saturation starting in early childhood. For those with hepatic cirrhosis, monitor for hepatocellular cancer with biannual abdominal ultrasound examination and serum alpha-fetoprotein concentration.

Agents/circumstances to avoid: Alcohol consumption; ingestion of iron-containing preparations and supplemental vitamin C; handling or eating uncooked shellfish or marine fish because of risk of fatal septicemia from the marine bacterium V vulnificus.

Evaluation of relatives at risk: Biochemical testing (i.e., serum ferritin concentration and transferrin-iron saturation) or molecular genetic testing in relatives at risk before evidence of organ damage from iron overload; monitor sibs with annual measurement of serum ferritin concentration and transferrin-iron saturation starting in early childhood.

Genetic counseling. Juvenile hemochromatosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing are possible if both disease-causing mutations have been identified in the family; however, requests for prenatal testing for conditions which (like juvenile hereditary hemochromatosis) do not affect intellect and have effective treatment available are not common.

Diagnosis

Clinical Diagnosis

Juvenile hemochromatosis (JHH) should be suspected in any child, adolescent, or young adult with findings of iron overload; such findings include the following:

  • Hypogonadotropic hypogonadism
  • Hepatomegaly
  • Hepatic cirrhosis
  • Hepatocellular carcinoma
  • Diabetes mellitus
  • Cardiomyopathy
  • Arrhythmias
  • Arthritis
  • Progressive increase in skin pigmentation

Many of these features are evident before age 30 years.

Presenting symptoms in the first or second decade may be less specific; they include lack of appetite, fatigue, amenorrhea, or arthralgia.

Testing

Biochemical testing. Data are limited as documented cases of juvenile hemochromatosis are rare; however, the following two biochemical measurements should be performed:

  • Serum ferritin concentration, which ranges from 1000 to 7000 µg/L in affected individuals (normal: 20-260 µg/L for male children/adolescents; 5-140 µg/L for female children/adolescents, 25-300 µg/L for adult males, and 25-200 µg/L for adult females)
  • Transferrin-iron saturation, which is typically very high, often reaching 100% (normal: 15%-50% in children/adolescents; ~ 33% in adults)

Imaging

  • Magnetic resonance imaging (MRI) has become a valuable noninvasive technique to quantify hepatic iron overload [Gandon et al 2004].
  • Superconducting quantum interference device (SQUID) is a noninvasive method for quantifying liver iron biomagnetometry [Fung et al 2004].

Liver biopsy. A hepatic iron index of higher than 1.9 suggests iron overload in HFE-associated hereditary hemochromatosis. Similarly, because iron overload is more severe in juvenile hemochromatosis, an index of higher than 1.9 also applies for juvenile hemochromatosis (normal: <1.0) [Pietrangelo 2004].

Molecular Genetic Testing

Genes. Mutation of two genes is currently known to cause juvenile hemochromatosis:

  • HJV (HFE2) (locus name HJV [HFE2A]) encoding hemojuvelin, accounts for more than 90% of cases reported to date.
  • HAMP (HEPC) (locus name HFE2B) encoding hepcidin, accounts for fewer than 10% of cases reported to date.

Clinical testing

HJV

  • Sequence analysis or mutation scanning detects mutations in more than 98% of individuals with HJV-related juvenile hemochromatosis. Neither sequence analysis nor mutation scanning detects exonic or whole-gene deletions.
  • Targeted mutation analysis. To date, the most frequently reported mutation in HJV is p.Gly320Val; it accounted for two-thirds of mutations identified in the original HJV positional cloning report [Papanikolaou et al 2004]. The p.Gly320Val mutation was identified in all French-Canadian individuals with juvenile hemochromatosis phenotypes from the Saguenay-Lac-Saint-Jean region [Lanzara et al 2004].

HAMP

  • Sequence analysis or mutation scanning detects mutations in more than 98% of individuals with HAMP-related juvenile hemochromatosis. Neither sequence analysis nor mutation scanning detects exonic or whole-gene deletions.

Table 1. Summary of Molecular Genetic Testing Used in Juvenile Hereditary Hemochromatosis (JHH)

Gene SymbolProportion of JHH Caused by Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency 1
HJV>90%Targeted mutation analysisp.Gly320ValSee footnote 2
Sequence analysis / mutation scanning 3Sequence variants 4>98%
HAMP<10%Sequence analysis / mutation scanning 3Sequence variants 4>98%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Most frequently reported mutation [Papanikolaou et al 2004]; identified in all affected French-Canadian individuals from the Saguenay-Lac-Saint-Jean region [Lanzara et al 2004]

3. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Testing Strategy

To establish the diagnosis of juvenile hemochromatosis in a proband, the following tests are used:

  • Biochemical testing (high serum ferritin concentration; high transferrin-iron saturation)
  • Molecular testing of HJV and HAMP
  • If homozygous or compound heterozygous mutations are not identified in either HJV or HAMP, consider testing for HFE-associated hemochromatosis. However, the clinical relevance of identifying one mutation in HJV or HAMP and HFE or two mutations in HFE and one in one of the other two genes is unknown. (See Differential Diagnosis.)
  • Hepatic imaging
  • Possible liver biopsy

    Note: Liver biopsy is usually used for prognostication (see Management); however, it may be used infrequently for diagnosis. Guidelines for biopsy are not defined for JHH.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Juvenile hemochromatosis (JHH) is characterized by early onset of severe iron overload. Juvenile hemochromatosis typically presents in the first to third decade of life; however, the adult presentation of three individuals with HJV mutations [Koyama et al 2005] highlights the wide spectrum of disease phenotypes related to HJV mutations: from classic JHH at one extreme to late onset adult form at the other extreme.

Males and females are equally affected.

In clinical practice, individuals with juvenile hemochromatosis are rarely diagnosed before significant iron overload occurs.

Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis. Osteopenia and osteoporosis are common complications in individuals with prolonged hypogonadism [Vaiopoulos et al 2003]. The clinical course is severe, with the main cause of death being cardiac-related disease [De Gobbi et al 2002]. The prevalence of cardiac disease is strikingly high and in some instances is the presenting finding [Filali et al 2004].

Although individuals with juvenile hemochromatosis may develop adrenocortical insufficiency or hypothyroidism, these complications are rare [Varkonyi et al 2000]. While diabetes is common in individuals with HFE-related hemochromatosis, the extent of glucose impairment in people with JHH has not been well defined. However, in one study of 26 patients from 20 families with JHH, reduced glucose tolerance was identified in 58% [De Gobbi et al 2002].

Despite the more severe iron overload seen in juvenile hemochromatosis (as compared to HFE-associated hereditary hemochromatosis), hepatocellular cancer has not been reported in juvenile hemochromatosis [Camaschella et al 2002]; a possible explanation is that untreated individuals with juvenile hemochromatosis die prematurely as a result of cardiac complications [Camaschella 1998].

If juvenile hemochromatosis is detected early enough and blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported with HJV-related juvenile hemochromatosis or HAMP-related juvenile hemochromatosis; the clinical and biochemical phenotypes reported for all mutations identified so far appear similar.

Koyama et al [2005] reported three Japanese individuals (two from the same family) presenting around age 50 years with typical clinical signs of JHH and hepatic histologic damage compatible with hemochromatosis. All three were homozygous for an HJV mutation.

  • One was homozygous for the novel missense mutation 745G>C (p.Asp249His), suggesting that the mutation, which results in a relatively mild late-onset phenotype, may not be highly detrimental to hemojuvelin functioning.
  • The two from the same family were homozygous for another novel mutation, 934C>T (p.Gln312X), which induced a premature stop codon, suggesting that unidentified factor(s) in this family may modify the clinical phenotype, as other truncating mutations typically have a more severe clinical presentation.

In a given individual, the degree of iron loading and the resultant clinical severity ultimately depends on the combination of genetic and environmental load. For example:

  • Brakensiek et al [2009] reported a male with severe JHH who died at age 21 years as a result of severe cardiomyopathy resulting from excessive iron loading. He was homozygous for the common HJV mutation p.Gly320Val, compound heterozygous for the HFE mutations p.His63Asp and p.Ser65Cys, and homozygous for the HFE mutation IVS2+4T>C, leading the authors to hypothesize that the HFE mutations may have exacerbated the clinical phenotype in this patient.
  • Gehrke et al [2005] observed that an individual who was homozygous for the HJV mutation p.Gly320Val and heterozygous for the HFE mutation p.Cys282Tyr had a more severe phenotype.

Nomenclature

Despite use of the locus names HFE2A and HFE2B for the two juvenile hemochromatosis genes, and use of the gene symbol HFE2 for HJV (one of the two juvenile hemochromatosis-related genes), juvenile hemochromatosis is not associated with mutations in HFE in which mutations cause HFE-associated hereditary hemochromatosis, an adult-onset disorder of iron storage.

To avoid confusion, all researchers/physicians now prefer to use the locus name HJV and the gene symbol HJV for the common juvenile hemochromatosis gene that encodes hemojuvelin.

Prevalence

Juvenile hemochromatosis is rare.

Affected individuals have been reported worldwide.

Mutations in HJV represent the majority of worldwide cases of juvenile hemochromatosis. To date, HJV-related juvenile hemochromatosis has been reported in individuals of Northern European (including Canadian, American, and Australian) ethnicities; Italian, Greek, Dutch, Albanian, Hungarian, Romanian, Japanese, and Chinese descent; and in the French-Canadian region of Saguenay-Lac-Saint-Jean. No particular ethnic background appears to have a higher frequency; however, a clustering of HJV mutations occurs in Italy and Greece.

A much smaller number of individuals of Italian, Greek, Arab, and Portuguese descent with HAMP-related juvenile hemochromatosis have been reported.

Differential Diagnosis

Iron overload phenotypes can be primary or secondary.

Primary iron overload phenotypes include the following:

  • HFE-associated hereditary hemochromatosis (adult-onset classic hemochromatosis, type 1 hemochromatosis, HFE1). At the milder end of the spectrum, classic hereditary hemochromatosis is known to be caused by homozygous mutations in HFE, with clinical features typically presenting in the 40s to 50s in contrast to juvenile hemochromatosis, which typically presents before age 30 years. HFE-associated hereditary hemochromatosis, considered the classic and most common form, has many features in common with juvenile hemochromatosis, including hypogonadotropic hypogonadism, cardiomyopathy, diabetes mellitus, hepatic cirrhosis, and skin hyperpigmentation; however, the clinical findings of juvenile hemochromatosis are much more severe than those seen in classic hereditary hemochromatosis because of the much higher rate of iron accumulation in the former. In particular, in juvenile hemochromatosis the clinical features of hypogonadotropic hypogonadism and cardiomyopathy are more prominent than those in classic hereditary hemochromatosis [Camaschella et al 2002]. Classic hereditary hemochromatosis is caused by increased intestinal iron absorption as a result of a defect in the HFE protein.

    Controversy exists as to the exact penetrance of hereditary hemochromatosis, although it is widely accepted that classic hereditary hemochromatosis, in contrast to juvenile hemochromatosis, is a low-penetrant disorder. In both juvenile hemochromatosis and classic hereditary hemochromatosis, macrophages are iron depleted despite total body iron excess.

    An intermediate iron overload phenotype has been described in individuals with digenic inheritance of heterozygous mutations in HAMP and HFE or heterozygous mutations in HJV and HFE. The reports suggest that an explanation for the low penetrance rate in classic hereditary hemochromatosis is the need for genetic modifiers, such as mutations in HJV and HAMP, in addition to mutations in HFE to produce the classic hereditary hemochromatosis disease phenotype. However, because digenic inheritance accounts for a small proportion of individuals with classic HFE-associated hereditary hemochromatosis reported to date, other mechanisms are likely to modify penetrance. Further investigation of the importance of HJV, HAMP, HFE, and other iron metabolism-related alleles in the clinical expression of iron overload is warranted [Lee et al 2002, Merryweather-Clarke et al 2003, Lanzara et al 2004, Lee et al 2004a, Lee et al 2004b, Le Gac et al 2004, Majore et al 2004, Pietrangelo 2004].
  • TFR2 (transferrin receptor 2)-related hemochromatosis (type 3 hemochromatosis, HFE3). The iron overload phenotype is variable: in some families, adult onset (similar to that seen in classic HFE-associated hereditary hemochromatosis) is observed; in others, the onset occurs before adulthood but later than in juvenile-onset hemochromatosis [Camaschella et al 2000, Le Gac et al 2004].
  • HFE (p.Cys282Tyr/p.His63Asp compound heterozygosity) and transferrin receptor 2 (p.Gln317X homozygosity). A few individuals clinically diagnosed with juvenile hemochromatosis have not had mutations in either HJV or HAMP. In a family with typical clinical findings of JHH in adolescence, no mutations were identified in either HJV or HAMP; affected individuals were compound heterozygotes for the HFE mutations p.Cys282Tyr/p.His63Asp and homozygous for the TFR2 mutation p.Gln317X [Pietrangelo et al 2005].
  • Ferroportin (SLC40A1)-related iron overload (ferroportin disease; type 4 hemochromatosis, HFE4): Individuals with mutations in the gene encoding ferroportin also have iron overload; however, unlike individuals with juvenile hemochromatosis and classic HFE-associated hereditary hemochromatosis, they show macrophages that are iron laden. Affected individuals have high serum ferritin concentration despite normal/low transferrin-iron saturation at early stages of the disease. Mild anemia can accompany the disease. Anemia may occur early in therapeutic phlebotomy. Ferroportin-related iron overload presents in adulthood and is transmitted in an autosomal dominant manner [Montosi et al 2001, Njajou et al 2001].
  • It is now apparent that different SLC40A1 mutations can culminate in different iron overload phenotypes [De Domenico et al 2006]. Ferroportin mutant proteins can be divided into the following two main classes:
    • Proteins that fail to localize to the cell surface and are thus unable to export iron. Affected individuals have typical ferroportin disease with low transferrin saturation and early Küpffer cell iron loading
    • Proteins that localize to the cell surface but are not responsive to the hepcidin (i.e., the cells show hepcidin resistance). Affected individuals have high transferrin saturation and early hepatocyte iron loading similar to classic HFE-associated hereditary hemochromatosis [De Domenico et al 2006].
  • Neonatal hemochromatosis. Iron overload occurs in utero. This severe, often fatal iron overload syndrome usually presents at birth. Inheritance is unknown; however, autosomal recessive and mitochondrial inheritance have been postulated. No genetic locus has been identified. It has recently been suggested that the fetal liver injury that characterizes neonatal hemochromatosis is the result of maternal alloimmunity. This suggestion is supported by the observation that recurrence rates in families with neonatal hemochromatosis are far greater (≥90%) than would be predicted by Mendelian inheritance. Furthermore, in women with a history of pregnancy resulting in neonatal hemochromatosis, treatment with high-dose IVIG reduced the risk of having a severely affected child [Whitington & Malladi 2005, Whitington & Kelly 2008, Rand et al 2009].
  • Atransferrinemia. Atransferrinemia is characterized by absent transferrin and, therefore, an inability to deliver iron to the red cell precursors in the bone marrow. This lack of iron for the red cell precursors sets up a powerful erythroid drive with massive intestinal hyperabsorption of iron. Affected individuals are iron overloaded, yet have a microcytic anemia. This condition is an exceedingly rare autosomal recessive disorder, with only a few individuals reported worldwide. Hypotransferrinemia is a milder phenotype that is allelic with atransferrinemia.

Secondary disorders of iron overload include the following:

  • African iron overload. African iron overload occurs in individuals with a predisposition to iron overload that is exacerbated by excessive intake of dietary iron. It is particularly prevalent among Africans who drink a traditional beer brewed in non-galvanized steel drums. In the past, African iron overload was mainly attributed to dietary excess alone. However, serious iron overload does not develop in all beer drinkers, and not all individuals with iron overload consume excessive amounts of the beer, suggesting that other yet-to-be defined iron-related genes predispose to the condition. A specific mutation (p.Gln248His) in SCL40A1, the gene encoding ferroportin 1, has been associated with tendency to iron overload in Africans and African Americans [Beutler et al 2003, Gordeuk et al 2003].
  • Transfusional iron overload. Individuals receiving red blood cell transfusions or any products containing red blood cells on a regular basis develop iron overload as a result of the transfused iron.
  • Nontransfusional iron overload. Nontransfusional iron overload can occur in conditions in which ongoing erythroid destruction generates an erythroid drive signaling intestinal iron hyperabsorption. For example, iron overload is a feature in beta-thalassemia intermedia, for which most affected individuals are not transfused. Other examples include congenital dyserythropoetic anemia and sideroblastic anemia.

Disorders of excess ferritin without iron overload include the following:

  • Hyperferritinemia cataract syndrome (HCS). Individuals with HCS do not have iron overload. They have very high serum ferritin concentration caused by a mutation in the iron-responsive element in the 5' untranslated region of the gene encoding the ferritin light chain that leads to inappropriate excessive production of ferritin. Transferrin-iron saturation is normal. Individuals with HCS have early-onset bilateral (often congenital) cataracts. Phlebotomy is contraindicated in these individuals [Girelli et al 1995, Aguilar-Martinez et al 1996].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with juvenile hemochromatosis, the following evaluations are recommended:

  • Serum iron status. Measurements of serum iron concentration, total iron binding capacity, transferrin saturation, and serum ferritin concentration
  • Pituitary-gonadal axis. Recording of signs and symptoms of hypogonadotropic hypogonadism and measurement of serum concentration of gonadotropins (i.e., FSH, LH) (pituitary gland) and testosterone (testes) or estradiol (ovaries). In several clinical situations, a dynamic evaluation of the pituitary-gonadal axis is required, consisting mainly of a GnRH (gonadotropic releasing hormone) stimulation test. Pituitary MRI may be considered in some cases.
  • Affected joints. Radiographic evaluation
  • Bone mineral density. Dual photon absorptiometry of the lumbar spine
  • Cardiac manifestations. ECG, transthoracic echocardiogram. In individuals without overt clinical manifestations of cardiac failure or arrhythmias, findings suggestive of left ventricular diastolic dysfunction (reduced left ventricular compliance) often precede evidence of ventricular dilatation and compromised ejection fraction.
  • Liver function. Liver histology to determine the extent of liver damage. Documentation of the presence or absence of cirrhosis is of prognostic significance. Current recommendations for HFE-associated classic hereditary hemochromatosis are that HFE p.Cys282Tyr homozygotes with serum ferritin concentration lower than 1000 ng/mL and/or normal liver function enzymes need not be biopsied. Liver biopsy should be considered for individuals with higher serum ferritin concentrations and/or raised liver function enzymes in order to establish prognosis [Morrison et al 2003]. Because of the rarity of juvenile hemochromatosis, a specific protocol for individuals with juvenile hemochromatosis is not available, but adaptation of the classic HFE-associated hereditary hemochromatosis recommendation is a reasonable approach.
  • Diabetes mellitus. Screening for diabetes mellitus by overnight fasting plasma glucose measurement and, when indicated, by oral glucose tolerance test.

Treatment of Manifestations

Management and treatment recommendations for juvenile hemochromatosis stated here are based on the established HFE-associated hemochromatosis recommendations when specific juvenile hemochromatosis information may not exist.

Treatment of iron overload. Phlebotomy is the therapy of choice in juvenile hemochromatosis and follows the same principles as the treatment of classic HFE-associated hemochromatosis. It is simple, safe, and effective. Affected individuals should be encouraged to follow a regimen of phlebotomy of one unit of blood once or twice weekly [Tavill 2001]. Approximately 200 mg of iron are removed per unit of blood depending on the individual's hematocrit. Because individuals with juvenile hemochromatosis are usually severely iron overloaded, a therapeutic regimen of one to two weekly phlebotomies may take up to two to three years to reduce iron stores to desired levels.

The hematocrit should be monitored prior to phlebotomy; phlebotomy should be postponed if the hematocrit drops more than 20% of its initial value [Tavill 2001]. Systematic administration of erythropoietin has been successful in maintaining the hematocrit in individuals who failed to mount an adequate bone marrow response to the phlebotomy regimen [De Gobbi et al 2000].

Serum ferritin concentration reflects body iron stores and is used to monitor the progress of therapy; it is expected to fall progressively, along with iron mobilization. Measuring serum ferritin concentration every 10-12 phlebotomies is reasonable; however, once serum ferritin concentration is below 100 ng/mL, it should be measured more often, ideally prior to each phlebotomy. Achievement of serum ferritin concentration below 50 ng/mL and restoration of normal transferrin-iron saturation indicates the end point of the intensive phlebotomy treatment.

Maintenance therapy. The frequency of phlebotomies is adjusted to maintain normal serum ferritin concentration and transferrin-iron saturation. When iron removal is not urgent, phlebotomies could be spaced further apart according to the responsiveness of the bone marrow to restore adequate hematocrit. Usually four to six phlebotomies annually are sufficient. The individual should permanently continue on this schedule of phlebotomy maintenance therapy.

Iron chelators such as parenteral deferoxamine (Desferal®) are used to treat individuals with secondary iron overload. They are not recommended in the treatment of juvenile hemochromatosis unless the disease is complicated by concomitant anemia or severe cardiac failure. In the latter situation, administration of deferoxamine alone or in combination with deferiprone can reduce mortality by improving left ventricular ejection fraction [Kelly et al 1998, Fabio et al 2007].

Treatment of secondary complications. Treatment does not essentially differ from the conventional treatment applied in other situations:

  • Hypogonadotropic hypogonadism is generally considered irreversible, despite adequate iron removal. However, reversal of hypogonadism has been observed in some young individuals who have been successfully treated with phlebotomy or iron chelation [Angelopoulos et al 2005]. For the majority of individuals with hypogonadism, testosterone or hormone replacement therapy (HRT) is required to improve symptoms and prevent the development of secondary osteopenia or osteoporosis [Angelopoulos et al 2006].
  • Transdermal preparations (i.e., patches) deliver testosterone or estradiol at a controlled rate into the systemic circulation, avoiding first-pass hepatic metabolism; therefore, this approach may be useful for individuals with juvenile hemochromatosis, eliminating the risk of potential liver complications.
  • Administration of gonadotropins has restored fertility and has led to a twin pregnancy in a woman with juvenile hemochromatosis.
  • Arthropathy is not modified by treatment. Individuals with juvenile hemochromatosis have to cope with persistent arthralgia presenting at a young age. Painful joints may require treatment with salicylates or nonsteroidal anti-inflammatory drugs (NSAIDS) [Vaiopoulos et al 2003].
  • Severe cardiac failure is treated with ACE inhibitors, diuretics, cardiac glycosides, and possibly deferoxamine. If left untreated, cardiac disease progresses rapidly and becomes refractory to treatment, leading to death in most cases. Orthotopic heart transplantation has been used on occasion [Caines et al 2005].
  • Liver steatosis and fibrosis are treated with appropriately early phlebotomy [Camaschella et al 2002]; however, it is uncertain whether these features are reversible. Reversibility of liver fibrosis has been reported in individuals treated for HFE-associated hemochromatosis [Falize et al 2006].

    Cirrhosis is thought to be irreversible despite iron removal. Individuals with cirrhosis should undergo endoscopic evaluation to document the presence of varices and should be treated with propranolol or nadolol, as indicated. In advanced disease, orthotopic liver transplantation (OLT) could be considered. Of note, individuals with hereditary hemochromatosis undergoing OLT display an overall lower survival than individuals undergoing OLTs for other causes of liver disease. Because most post-transplantation deaths occur in the perioperative period from cardiac disease or infection, it is advisable to remove as much of excess iron stores as possible before OLT even though the effect of excess tissue iron on survival post-OLT is not known [Tavill 2001].
  • Diabetes mellitus may require insulin administration; successful iron removal may improve its course [Angelopoulos et al 2007].

Prevention of Primary Manifestations

Individuals with biochemical evidence of iron overload but without evidence of organ dysfunction or failure should be encouraged to undergo regular phlebotomies until excess iron stores are depleted to prevent the development of complications associated with excess iron stores.

Treatment by phlebotomy in presymptomatic stages can prevent organ damage.

Prevention of Secondary Complications

HRT prevents the development of osteoporosis.

Surveillance

Whenever hepatic cirrhosis is identified, monitoring for hepatocellular cancer is recommended. Most hepatologists propose twice-yearly screening with abdominal ultrasound examination and serum alpha-fetoprotein concentration [Tavill 2001].

Agents/Circumstances to Avoid

Avoid the following:

  • Alcohol consumption, which has a synergistic effect with iron-induced liver damage in individuals with liver damage
  • Iron-containing preparations and supplemental vitamin C
  • Handling or eating uncooked shellfish or marine fish, because of susceptibility to fatal septicemia from the marine bacterium V vulnificus

Evaluation of Relatives at Risk

Once a diagnosis of JHH has been made in a family, all at-risk family members (i.e., sibs) should be tested for the mutations identified in the affected individual. Family members with two HJV or HAMP mutations should be followed from early childhood with annual measurement of serum ferritin concentration and transferrin iron saturation to monitor for the development of iron overload.

If a molecular diagnosis was not made or the genetic status of the sibs of an affected individual is unknown, the sibs should be followed from early childhood with annual measurement of serum ferritin concentration and transferrin iron saturation to monitor for the development of iron overload.

If juvenile hemochromatosis is detected before evidence of organ damage, either by molecular genetic testing in relatives at-risk or by biochemical testing (i.e., serum ferritin concentration and transferrin-iron saturation), treatment via phlebotomy can reverse or prevent many of the secondary complications resulting from organ damage.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

All pregnant women with JHH should be under the care of a maternal-fetal medicine specialist, an endocrinologist, and a cardiologist. Preferably women with JHH should be seen by these specialists prior to becoming pregnant.

Pregnancy in women with untreated JHH is high risk because the increased hemodynamic burden of pregnancy can precipitate cardiac failure in women with an underlying cardiomyopathy. Of note, it is critically important for specialists in endocrinology and infertility to be aware of JHH as a cause of infertility and to evaluate patients for iron overload prior to correcting the underlying hormonal imbalance. In a case report, a young woman who became pregnant following correction of her hypogonadotropic hypogonadism developed fatal cardiogenic shock; she was only identified as having JHH with severe iron overload at the time of presentation of her heart disease [Filali et al 2004].

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Juvenile hemochromatosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with juvenile hemochromatosis are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of at-risk family members using molecular genetic techniques is possible if both disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Use of samples that have been banked should be explicitly approved in a written, revocable consent by each person from whom the sample is obtained. Such consents should detail all known potential biologic, ethical, social, and legal risks and their implications.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like juvenile hemochromatosis) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canadian Hemochromatosis Society
    7000 Minoru Boulevard
    Suite 272
    Richmond British Columbia V6Y 3Z5
    Canada
    Phone: 877-223-4766 (toll-free); 604-279-7135
    Fax: 604-279-7138
    Email: office@toomuchiron.ca
  • Iron Disorders Institute (IDI)
    PO Box 675
    Taylors SC 29687
    Phone: 888-565-4766 (Toll-free Information Request Line); 864-292-1175
    Fax: 864-292-1878
    Email: info@irondisorders.org
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Juvenile Hereditary Hemochromatosis: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HFE2BHAMP19q13​.12HepcidinHAMP @ LOVDHAMP
HJVHFE21q21​.1HemojuvelinHFE2 @ LOVDHFE2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Juvenile Hereditary Hemochromatosis (View All in OMIM)

602390HEMOCHROMATOSIS, TYPE 2A; HFE2A
606464HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP
608374HEMOJUVELIN
613313HEMOCHROMATOSIS, TYPE 2B; HFE2B

HJV (HFE2)

Normal allelic variants. HJV comprises four exons. The first exon is not translated. Multiple alternate splicing has been observed with five potential transcripts defined. The mRNA is 2.2 kb in size and is highly expressed in liver, skeletal, and cardiac muscle.

Pathologic allelic variants. Over 30 different HJV mutations, all in the coding region, have been identified so far in either homozygous or compound heterozygous form. The majority of mutations appear to be private; however, the HJV mutation p.Gly320Val is the most prevalent mutation reported to date representing more than 50% of all detected mutations in affected individuals worldwide.

Normal gene product. The full-length hemojuvelin protein comprising 426 amino acids is predicted to be approximately 41 kd in size. Bioinformatic analyses revealed that a 35-amino acid hydrophobic signal peptide is at the N-terminal. At the C-terminal, a transmembrane domain and a glycophosphatidyl inositol (GPI) addition signal sequence exist. The GPI anchor is functional in vitro [Zhang et al 2005]. At position 98, a tri-amino-acid RGD (Arg-Gly-Asp) domain is thought to be important in cell adhesion. A partial vWF-like domain spans the central portion of the protein (aa 167-253). Several cleavage sites are predicted in hemojuvelin including furin and repulsive guidance molecule (RGM) autocatalytic sites. Overall, the hemojuvelin protein is about 91% homologous to RGM type C in mouse.

Two isoforms of hemojuvelin have been identified: the full length protein and the disulphide bonded N- and C-terminal chains of hemojuvelin cleaved at the Asp-Pro RGM autocatalytic cleavage site. A soluble form of hemojuvelin is released or secreted and competes with the membrane-bound form of hemojuvelin [Lin et al 2005]. Iron modulates the release of soluble hemojuvelin [Lin et al 2005, Silvestri et al 2007, Zhang et al 2007], and in primary hepatocytes increasing amounts of soluble hemojuvelin reduced hepcidin mRNA expression [Lin et al 2005].

Hemojuvelin is a key upstream regulator of hepcidin expression. Hemojuvelin acts as a coreceptor for bone morphogenetic protein (BMP) signaling in the hepatocyte [Babitt et al 2006], signaling via BMP receptors and SMADs. Binding of BMPs to their receptor results in the phosphorylation of downstream receptor SMADs including SMAD 1, 5, and 8. In turn these bind to SMAD4, the terminal transcriptional effector critical for mediating hemojuvelin/BMP induction of hepcidin [Wang et al 2005]. Recently, BMP6 has been shown to be the critical regulator of hepcidin signaling through the BMP receptors [Andriopoulos et al 2009, Meynard et al 2009].

Membrane bound hemojuvelin is regulated by the serine protease matriptase-2, with hemojuvelin being a key substrate for the proteolytic activity of matriptase-2. Mutations in TMPRSS6, encoding matriptase-2, underlie iron-refractory iron deficiency anemia (IRIDA), an inherited severe iron deficiency anemia caused by excess hepcidin levels [Finberg et al 2008]. People with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, because of a failure of matriptase2 to cleave hemojuvelin resulting in unregulated stimulation of hepcidin expression despite low iron levels [Lee 2009].

Abnormal gene product. Individuals with mutations in hemojuvelin have extremely low levels of hepcidin in urine, suggesting that hemojuvelin normally regulates hepcidin expression [Papanikolaou et al 2004]. Similarly, hepcidin levels are depressed in hemojuvelin knockout mice [Huang et al 2005, Niederkofler et al 2005]. Furthermore, siRNA knockdown of hemojuvelin resulted in decreased hepcidin mRNA expression in primary hepatocytes, underscoring hemojuvelin’s critical role in modulating hepcidin. Loss of hemojuvelin function results in decreased BMP signaling in the liver, with associated decreased hepcidin expression.

HAMP (HEPC)

Normal allelic variants. HAMP comprises three exons. Exon 3 encodes the active 25-amino acid peptide. The hepcidin mRNA is 0.4 kb in size.

Pathologic allelic variants: Six different mutations in HAMP causing juvenile hemochromatosis in six independent families have been reported to date [Roetto et al 2003, Delatycki et al 2004, Matthes et al 2004, Roetto et al 2004, Rideau et al 2007]. Mutations have been reported in both coding and non-coding regions of the gene.

Normal gene product. The 84-amino acid pre-protein contains an N-terminal signal sequence (24 amino acid) and a penta arginyl proteolysis site, which is used to produce the active C-terminal 25-amino acid peptide. The active peptide comprises eight cysteines forming four disulfide bridges. As hepcidin is a small peptide, it is filtered by the kidney and detectable in the urine. Hepcidin is predominantly expressed in liver, and detected in much lower amounts in heart, brain, lung, and other tissues. Hepcidin functions as a key liver-produced hormone regulating intestinal iron absorption and macrophage iron release. Hepcidin interacts with ferroportin to mediate ferroportin internalization and subsequent degradation. When iron overload occurs, hepcidin is secreted and serves to limit plasma iron concentration by preventing iron uptake in the intestine and preventing iron release from macrophages. In contrast, in the clinical setting of iron deficiency, hepcidin is suppressed to allow intestinal iron absorption.

Abnormal gene product. Individuals with mutant hepcidin fail to prevent iron uptake in the intestine, resulting in iron overload. Macrophages are iron-depleted as a result of failure of hepcidin action.

References

Literature Cited

  1. Aguilar-Martinez P, Biron C, Masmejean C, Jeanjean P, Schved JF. A novel mutation in the iron responsive element of ferritin L-subunit gene as a cause for hereditary hyperferritinemia-cataract syndrome. Blood. 1996;88:1895. [PubMed: 8781450]
  2. Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482–7. [PMC free article: PMC2810136] [PubMed: 19252486]
  3. Angelopoulos N, Papanikolaou G, Noutsou M, Rombopoulos G, Goula A, Tolis G. Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature. Exp Clin Endocrinol Diabetes. 2007;115:192–7. [PubMed: 17427110]
  4. Angelopoulos NG, Goula A, Dimitriou E, Tolis G. Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis. Fertil Steril. 2005;84:1744. [PubMed: 16359978]
  5. Angelopoulos NG, Goula AK, Papanikolaou G, Tolis G. Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature. Osteoporos Int. 2006;17:150–5. [PubMed: 15997423]
  6. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–9. [PubMed: 16604073]
  7. Beutler E, Barton JC, Felitti VJ, Gelbart T, West C, Lee PL, Waalen J, Vulpe C. Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis. 2003;31:305–9. [PubMed: 14636643]
  8. Brakensiek K, Fegbeutel C, Mälzer M, Strüber M, Kreipe H, Stuhrmann M. Juvenile hemochromatosis due to homozygosity for the G320V mutation in the HJV gene with fatal outcome. Clin Genet. 2009;76:493–5. [PubMed: 19796184]
  9. Caines AE, Kpodonu J, Massad MG, Chaer R, Evans A, Lee JC, Geha AS. Cardiac transplantation in patients with iron overload cardiomyopathy. J Heart Lung Transplant. 2005;24:486–8. [PubMed: 15797753]
  10. Camaschella C. Juvenile haemochromatosis. Baillieres Clin Gastroenterol. 1998;12:227–35. [PubMed: 9890070]
  11. Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14–5. [PubMed: 10802645]
  12. Camaschella C, Roetto A, De Gobbi M. Juvenile hemochromatosis. Semin Hematol. 2002;39:242–8. [PubMed: 12382199]
  13. De Domenico I, Ward DM, Musci G, Kaplan J. Iron overload due to mutations in ferroportin. Haematologica. 2006;91:92–5. [PMC free article: PMC3718253] [PubMed: 16434376]
  14. De Gobbi M, Pasquero P, Brunello F, Paccotti P, Mazza U, Camaschella C. Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin. Haematologica. 2000;85:865–7. [PubMed: 10942934]
  15. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C. Natural history of juvenile haemochromatosis. Br J Haematol. 2002;117:973–9. [PubMed: 12060140]
  16. Delatycki MB, Allen KJ, Gow P, MacFarlane J, Radomski C, Thompson J, Hayden MR, Goldberg YP, Samuels ME. A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. Clin Genet. 2004;65:378–83. [PubMed: 15099344]
  17. Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood. 2007;109:362–4. [PubMed: 16960153]
  18. Falize L, Guillygomarc'h A, Perrin M, Laine F, Guyader D, Brissot P, Turlin B, Deugnier Y. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology. 2006;44:472–7. [PubMed: 16871557]
  19. Filali M, Le Jeunne C, Durand E, Grinda JM, Roetto A, Daraio F, Bruneval P, Jeunemaitre X, Gimenez-Roqueplo AP. Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis. 2004;33:120–4. [PubMed: 15315789]
  20. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, Fleming MD. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40:569–71. [PMC free article: PMC3104019] [PubMed: 18408718]
  21. Fung EB, Fischer R, Pakbaz Z, Fagaly RL, Vichinsky E, Starr TN, Ewing T, Paulson DN, Hassenzahl WV, Harmatz P. The new SQUID biosusceptometer at Oakland: first year of experience. Neurol Clin Neurophysiol. 2004;2004:5. [PubMed: 16012600]
  22. Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, Deugnier Y. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004;363:357–62. [PubMed: 15070565]
  23. Gehrke SG, Pietrangelo A, Kascák M, Braner A, Eisold M, Kulaksiz H, Herrmann T, Hebling U, Bents K, Gugler R, Stremmel W. HJV gene mutations in European patients with juvenile hemochromatosis. Clin Genet. 2005;67:425–8. [PubMed: 15811010]
  24. Girelli D, Corrocher R, Bisceglia L, Olivieri O, De Franceschi L, Zelante L, Gasparini P. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation") Blood. 1995;86:4050–3. [PubMed: 7492760]
  25. Gordeuk VR, Caleffi A, Corradini E, Ferrara F, Jones RA, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo IT, Gomo ZA, Moyo VM, Rouault TA, MacPhail P, Pietrangelo A. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis. 2003;31:299–304. [PubMed: 14636642]
  26. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115:2187–91. [PMC free article: PMC1180543] [PubMed: 16075059]
  27. Kelly AL, Rhodes DA, Roland JM, Schofield P, Cox TM. Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron-storage disease. QJM. 1998;91:607–18. [PubMed: 10024915]
  28. Koyama C, Hayashi H, Wakusawa S, Ueno T, Yano M, Katano Y, Goto H, Kidokoro R. Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene. J Hepatol. 2005;43:740–2. [PubMed: 16099526]
  29. Lanzara C, Roetto A, Daraio F, Rivard S, Ficarella R, Simard H, Cox TM, Cazzola M, Piperno A, Gimenez-Roqueplo AP, Grammatico P, Volinia S, Gasparini P, Camaschella C. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood. 2004;103:4317–21. [PubMed: 14982873]
  30. Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br J Haematol. 2004;125:674–8. [PubMed: 15147384]
  31. Lee P. Role of matriptase-2 (TMPRSS6) in iron metabolism. Acta Haematol. 2009;122:87–96. [PMC free article: PMC2855275] [PubMed: 19907145]
  32. Lee PL, Beutler E, Rao SV, Barton JC. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood. 2004a;103:4669–71. [PubMed: 14982867]
  33. Lee P, Gelbart T, West C, Halloran C, Beutler E. Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol Dis. 2002;29:471–87. [PubMed: 12547238]
  34. Lee PL, Barton JC, Brandhagen D, Beutler E. Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol. 2004b;127:224–9. [PubMed: 15461631]
  35. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106:2884–9. [PubMed: 15998830]
  36. Majore S, Binni F, Pennese A, De Santis A, Crisi A, Grammatico P. HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis. Hum Mutat. 2004;23:400. [PubMed: 15024747]
  37. Matthes T, Aguilar-Martinez P, Pizzi-Bosman L, Darbellay R, Rubbia-Brandt L, Giostra E, Michel M, Ganz T, Beris P. Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'UTR of the hepcidin gene. Blood. 2004;104:2181–3. [PubMed: 15198949]
  38. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VL, Livesey KJ, Tanphaichitr V, Rochette J, Robson KJ. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet. 2003;12:2241–7. [PubMed: 12915468]
  39. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41:478–81. [PubMed: 19252488]
  40. Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor CC, Gasparini P, Andrews NC, Pietrangelo A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619–23. [PMC free article: PMC209405] [PubMed: 11518736]
  41. Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-Serag HB, Gordon SC, Galan MV, Tung BY, Ioannou GN, Kowdley KV. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med. 2003;138:627–33. [PubMed: 12693884]
  42. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 2005;115:2180–6. [PMC free article: PMC1180556] [PubMed: 16075058]
  43. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, Snijders PJ, Rutten WP, Sandkuijl LA, Oostra BA, van Duijn CM, Heutink P. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28:213–4. [PubMed: 11431687]
  44. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77–82. [PubMed: 14647275]
  45. Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004;350:2383–97. [PubMed: 15175440]
  46. Pietrangelo A, Caleffi A, Henrion J, Ferrara F, Corradini E, Kulaksiz H, Stremmel W, Andreone P, Garuti C. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology. 2005;128:470–9. [PubMed: 15685557]
  47. Rideau A, Mangeat B, Matthes T, Trono D, Beris P. Molecular mechanism of hepcidin deficiency in a patient with juvenile hemochromatosis. Haematologica. 2007;92:127–8. [PubMed: 17229647]
  48. Roetto A, Daraio F, Porporato P, Caruso R, Cox TM, Cazzola M, Gasparini P, Piperno A, Camaschella C. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Blood. 2004;103:2407–9. [PubMed: 14630809]
  49. Rand EB, Karpen SJ, Kelly S, Mack CL, Malatack JJ, Sokol RJ, Whitington PF. Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. J Pediatr. 2009;155:566–71. [PubMed: 19560784]
  50. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21–2. [PubMed: 12469120]
  51. Silvestri L, Pagani A, Fazi C, Gerardi G, Levi S, Arosio P, Camaschella C. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood. 2007;109:4503–10. [PubMed: 17264300]
  52. Tavill AS. American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. Diagnosis and management of hemochromatosis. Hepatology. 2001;33:1321–8. [PubMed: 11343262]
  53. Vaiopoulos G, Papanikolaou G, Politou M, Jibreel I, Sakellaropoulos N, Loukopoulos D. Arthropathy in juvenile hemochromatosis. Arthritis Rheum. 2003;48:227–30. [PubMed: 12528123]
  54. Varkonyi J, Kaltwasser JP, Seidl C, Kollai G, Andrikovics H, Tordai A. A case of non-HFE juvenile haemochromatosis presenting with adrenocortical insufficiency. Br J Haematol. 2000;109:252–3. [PubMed: 10896410]
  55. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399–409. [PubMed: 16330325]
  56. Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem. 2007;282:12547–56. [PubMed: 17331953]
  57. Zhang AS, West AP, Wyman AE, Bjorkman PJ, Enns CA. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem. 2005;280:33885–94. [PubMed: 16103117]
  58. Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics. 2008; 121:e1615-21. [PubMed: 18474533]
  59. Whitington PF, Malladi P. Neonatal hemochromatosis: is it an alloimmune disease? J Pediatr Gastroenterol Nutr. 2005;40:544–9. [PubMed: 15861012]

Suggested Reading

  1. Brissot P, de Bels F. Current approaches to the management of hemochromatosis. Hematology Am Soc Hematol Educ Program. 2006:36–41. [PubMed: 17124037]
  2. Franchini M. Hereditary iron overload: update on pathophysiology, diagnosis, and treatment. Am J Hematol. 2006;81:202–9. [PubMed: 16493621]
  3. Gasparini P, Camaschella C. Hereditary hemochromatosis: is the gene race over? Eur J Hum Genet. 2004;12:341–2. [PubMed: 15094740]
  4. Nelson JE, Kowdley KV. Non-HFE hemochromatosis: genetics, pathogenesis, and clinical management. Curr Gastroenterol Rep. 2005;7:71–80. [PubMed: 15701302]
  5. Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, Loukopoulos D. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis. 2001;27:744–9. [PubMed: 11778658]
  6. Pissia M, Polonifi K, Politou M, Lilakos K, Sakellaropoulos N, Papanikolaou G. Prevalence of the G320V mutation of the HJV gene, associated with juvenile hemochromatosis, in Greece. Haematologica. 2004;89:742–3. [PubMed: 15194541]
  7. Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D'Adamo AP, Férec C, Camaschella C, Mura C, Roetto A, De Braekeleer M, Bechner L, Gasparini P. Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet. 2003;11:585–9. [PubMed: 12891378]
  8. Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D'Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C. Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet. 1999;64:1388–93. [PMC free article: PMC1377875] [PubMed: 10205270]

Chapter Notes

Author Notes

Web: www.xenon-pharma.com

Author History

Y Paul Goldberg, MB ChB, PhD, FRCPC (2004-present)
Julie MacFarlane, MS, CCGC; Xenon Pharmaceuticals Inc (2004-2011)
George Papanikalaou, MD, PhD; National and Kapodistrian University of Athens (2004-2011)

Revision History

  • 11 August 2011 (me) Comprehensive update posted live
  • 17 February 2005 (me) Review posted to live Web site
  • 12 July 2004 (pg) Original submission
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