Clinical characteristics.

TFR2-related hemochromatosis (TFR2-HC) is characterized by increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs. Age of onset is earlier than in HFE-related hemochromatosis. The majority of individuals present with signs and symptoms of iron overload in the third decade (e.g., weakness, fatigue, abdominal pain, hepatomegaly, arthritis, arthralgia, and progressive increase in skin pigmentation). Others present as young adults with nonspecific symptoms and abnormal serum iron studies or as adults with abnormal serum iron studies and signs of organ involvement including cirrhosis, diabetes mellitus, arthropathy, hypogonadism, cardiomyopathy, and increase in skin pigmentation.

Diagnosis/testing.

The diagnosis of TFR2-HC is established in a proband with biallelic pathogenic variants in TFR2 identified by molecular genetic testing.

Management.

Targeted therapy: In order to prevent iron overload-related complications, removal of excess iron by routine phlebotomy to maintain serum ferritin concentration at 50 ng/mL or lower and transferrin-iron saturation below 50%; iron chelation therapy as needed in those with anemia.

Supportive care: Vaccination for hepatitis A and B; therapy to prevent cirrhosis complications and liver decompensation including endoscopic surveillance of varices and prophylaxis with nonselective beta-blockers; salt restriction and diuretics for ascites with paracentesis and shunts as needed; antibiotics for spontaneous bacterial peritonitis; low protein diet for hepatic encephalopathy with lactulose and rifaximin as needed; hormone replacement therapy for hypogonadism; gonadotropins for fertility/pregnancy; routine treatment for diabetes mellitus and cardiac failure; nonsteroidal anti-inflammatory drugs and joint replacement for arthropathy.

Surveillance: Serum iron, transferrin, transferrin saturation, and ferritin concentration every six to 12 months once serum ferritin concentration is lower than 50 ng/mL. Serum AFP and liver ultrasound in individuals with cirrhosis every six months to assess for hepatic complications and for early detection of hepatocarcinoma. Individuals with hypogonadism, diabetes mellitus, and cardiac failure should have surveillance for complications related to the specific organ failure.

Agents/circumstances to avoid: Medicinal iron and nutritional supplements containing iron, excessive alcohol intake, vitamin C supplements, uncooked seafood, and lifestyle-related behaviors that increase the risk of viral hepatitis infection.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the TFR2 pathogenic variants found in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Pregnancy management: Phlebotomy can be paused in pregnant women with mild-to-moderate iron overload due to fetal utilization of maternal iron.

Genetic counseling.

TFR2-HC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TFR2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Once the TFR2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

TFR2-HC should be suspected in a proband with clinical features, symptoms, and laboratory features associated with iron overload in whom HFE-related hemochromatosis has been excluded.

Clinical features and symptoms of iron overload

• Weakness, chronic fatigue
• Abdominal pain
• Hepatomegaly
• Cirrhosis, hepatocellular carcinoma
• Endocrine manifestations, including diabetes mellitus, hypogonadotropic hypogonadism (decreased libido and impotence in men, amenorrhea in women)
• Cardiomyopathy, EKG abnormalities (conduction disturbances)
• Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
• Progressive increase in skin pigmentation

Laboratory features

• Transferrin saturation >45% (normal range: 20%-35% saturation in males and females)
• Serum ferritin concentration usually >200 µg/L in females and >300 µg/L in males. Normal ranges:
  • Children and adolescents: 15-150 µg/L
  • Adult females: 20-200 µg/L
  • Adult males: 20-300 µg/L
• Elevated liver enzymes and/or abnormal liver function tests
• Hyperglycemia

Liver biopsy. Findings on liver biopsy have been reported in some individuals with TFR2-HC [Bardou-Jacquet et al 2013, Joshi et al 2015, Badar et al 2016, Peters at al 2017, Sandhu et al 2018, Khayat et al 2019, Hernández et al 2021, Tang et al 2022]. Liver biopsy is used to assess:

• Histology; fibrosis or cirrhosis
• Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):
  • Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
  • Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
  • Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight

Imaging. Noninvasive techniques including MRI and SQUID (superconducting quantum interference device) developed to quantitate liver iron concentration have been applied to TFR2-HC [Biasiotto et al 2008, Joshi et al 2015, Badar et al 2016, Hernández et al 2021, Ravasi G et al 2021, Tang et al 2022]. Due to high installation and maintenance costs, clinical use of SQUID to quantitate liver iron may not be available.

Hepcidin evaluation. Individuals with TFR2-HC have decreased hepcidin concentrations in plasma and urine (similar to other types of autosomal recessive hemochromatosis). Hepcidin concentration in plasma and urine can be measured by mass-spectrometry-based assay and normalized for sex and age [Piubelli et al 2017].

Establishing the Diagnosis

The diagnosis of TFR2-HC is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TFR2 identified by molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

TFR2-related hemochromatosis (TFR2-HC) is characterized by deregulated, increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs [Camaschella & Poggiali 2009].

Age of onset in individuals with TFR2-HC is earlier than in individuals with HFE-related hemochromatosis (HFE-HC). Six individuals with childhood onset (range of onset: age 2-13 years) have been reported [Piperno et al 2004, Biasiotto et al 2008, Joshi et al 2015, Ravasi et al 2015, Khayat AA et al 2019], all with increased transferrin saturation and serum ferritin concentration. None of the children had clinical symptoms, except for fatigue in a 14-year-old boy [Joshi et al 2015]. Long-term follow up (>10 years) in two sibs diagnosed with TFR2-HC at age 12 and 13 years revealed no clinical features of iron overload when phlebotomy treatment was started early and continued over time [De Gobbi, unpublished data]. However, the majority of the individuals present with signs of iron overload from the third decade, as young adults with nonspecific symptoms and abnormal serum iron indices [Biasiotto et al 2008, Gérolami et al 2008, Del-Castillo-Rueda et al 2012, Peters et al 2017, Sandhu et al 2018] or as adults with abnormal serum iron studies and signs of organ involvement (e.g., liver fibrosis or cirrhosis, diabetes, hypogonadism, cardiomyopathy, and arthropathy) [Del-Castillo-Rueda et al 2012, Joshi et al 2015, Badar et al 2016, Peters et al 2017, Wang et al 2017, Sandhu et al 2018].

Liver disease. When TFR2-HC is progressive, complications can include cirrhosis and all its sequelae due to portal hypertension and liver dysfunction: ascites, varices and variceal bleeding, hypersplenism, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, coagulation disorders, and hepatocellular carcinoma (HCC). However, while the distribution of liver iron deposition is similar to that seen in HFE-HC (mainly in hepatocytes with a decreasing gradient from portal to centrolobular areas), HCC has not been observed in the limited number of affected individuals reported to date. Even in a large series of individuals with HCC, the subgroup with increased liver iron concentration did not have TFR2 pathogenic variants [Funakoshi et al 2016].

Endocrine manifestations. Hypogonadotropic hypogonadism usually starts during adolescence or between age 20 and 30 years and leads to decreased libido and impotence in men and amenorrhea in women. In men, additional clinical manifestations can include a decrease of androgen-dependent hair growth, testicular atrophy, and azoospermia. Severe hypogonadism is irreversible and requires lifelong hormone replacement therapy in males and females. Use of gonadotropins has successfully restored fertility and induced pregnancy in women who have been treated for other forms of hemochromatosis; no data are available regarding treatment for infertility in women with TFR2-HC. Diabetes mellitus results from loss of insulin secretory capacity due to iron-induced fibrosis of the islets of Langerhans and therefore requires treatment with insulin [Tang et al 2022]. When present, the onset of diabetes mellitus usually occurs between age 30 and 40 years. Iron removal via phlebotomy may improve control of diabetes mellitus but cannot reestablish normal glucose metabolism.

Cardiac manifestations. If present, cardiomyopathy is characterized by the classic features of cardiac dysfunction caused by increased deposition of iron: dilated cardiomyopathy with dilated ventricles and reduced fractional shortening resulting in reduced ejection fraction and predisposition to arrhythmias. In the advanced stage of cardiac involvement, EKG abnormalities can be present (low QRS complex voltage and nonspecific ST and T wave), and iron deposition in the conduction system may cause atrioventricular blocks. The common signs and symptoms of congestive heart failure are present and should be managed with standard medical therapy for heart failure. An implantable cardioverter defibrillator for prevention of fatal arrythmias can be used in those with severe cardiac disease. Lowering myocardial iron content through phlebotomy or iron chelation can improve left ventricular function.

Joint manifestations. Severe joint involvement has been reported [Ricerca et al 2009, Peters et al 2017]. Arthralgia can involve multiple sites but mainly affects metacarpophalangeal joints causing severe pain, deformation of hands, and functional impairment. After arthritis and arthralgia have developed progressive structural damage may continue even after the removal of systemic iron excess with phlebotomy. Some individuals have required joint replacement for severe joint disease.

Prognosis. Disease progression is slower than in juvenile hereditary hemochromatosis [De Gobbi et al 2002]. If TFR2-HC is diagnosed early and treated appropriately with phlebotomy, individuals with TFR2-HC will have normal life expectancy. Similar to HFE-HC, the most important factors that can influence survival are the onset of cirrhosis, diabetes, and/or cardiomyopathy.

Genotype-Phenotype Correlations

The limited number of individuals reported and the private nature of the pathogenic variants do not permit genotype-phenotype correlations.

Inheritance of compound heterozygosity for the HFE pathogenic variants p.Cys282Tyr (NM_000410.3:c.845G>A) and p.His63Asp and homozygosity for the TFR2 pathogenic variant p.Gln317Ter produced a phenotype of juvenile hemochromatosis in a single family [Pietrangelo et al 2005].

Individuals with TFR2-HC who are also heterozygous for an HFE pathogenic variant do not seem to have a more severe phenotype. In fact, a male homozygous for TFR2 pathogenic variant p.Trp781Ter and heterozygous for HFE pathogenic variant p.Cys282Tyr presented at age 46 years with a classic TFR2-HC phenotype (hyperferritinemia, severe hepatic iron accumulation detected by MRI, and chronic arthropathy) [Hernández et al 2021].

Penetrance

The penetrance of TFR2-HC is less than 100% and can be influenced by genetic (e.g., hemoglobinopathies) or environmental factors (e.g., chronic hepatitis, low dietary iron intake, and chronic bleeding). The oldest individual to be diagnosed with TFR2-HC is an individual diagnosed at age 82 years homozygous for TFR2 variant p.Arg30ProfsTer31 [Roetto et al 2001]. The youngest individual is a child with Alagille syndrome and homozygous for TFR2 pathogenic variant p.Ser470Ile diagnosed with iron overload at age two years [Khayat et al 2019]. In a family reported by Roetto et al [2001], one middle-aged female homozygous for TFR2 pathogenic variant p.Arg30ProfsTer31 had iron deficiency and a history of low dietary iron intake and hypermenorrhea. Girelli et al [2002] also found iron deficiency in a young female homozygous for p.Ala621_Gln624del who had a history of anorexia and Helicobacter pylori-related chronic gastritis.

Nomenclature

TFR2-HC is also known as hemochromatosis type 3 or HFE3; however, the term "HFE3" seems inappropriate because HFE has no role in TFR2-HC. "TFR2-related hemochromatosis" is the preferred term in the hemochromatosis classification developed by the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) [Girelli et al 2022].

Prevalence

TFR2-HC is rare, with pathogenic allele frequencies estimated within the range of 0.000008 to 0.0002 [Wallace & Subramaniam 2016]. Just over 50 affected individuals have been reported worldwide, most commonly of European descent (mainly in Italy but also in France, Portugal, and Spain). According to Sandhu et al [2018], the most frequent TFR2 pathogenic variants are p.Tyr250Ter, p.Glu60Ter, and p.Met172Lys. In individuals from Sicily, allelic frequency of p.Tyr250Ter was estimated to be 0.45% [De Gobbi et al 2001].

In Japan, where hemochromatosis is rare and heterogeneous, it has been proposed that TFR2-HC is the most frequent form of hereditary hemochromatosis [Hayashi et al 2006]; however, studies are limited. The most frequent pathogenic variant in individuals of Japanese descent is p.Ala621_Gln624del.

Primary Iron Overload Disorders

Genes associated with primary overload disorders (i.e., disorders characterized by increased absorption of iron from a normal diet) are listed in Table 2.

No studies have evaluated the prevalence of TFR2 pathogenic variants in individuals with non-HFE-related hemochromatosis.

Primary overload disorders of unknown genetic cause:

• African iron overload (OMIM 601195). Similar to TFR2-HC, African iron overload is associated with liver iron accumulation in reticuloendothelial and parenchymal cells and cirrhosis. Distinguishing features of African iron overload include susceptibility to tuberculosis and other infections and a lower frequency of cardiomyopathy and diabetes. African iron overload is characteristically diagnosed in individuals with an excessive intake of dietary iron from drinking beer brewed in non-galvanized steel drums and a genetic predisposition to iron loading (the molecular basis underlying this predisposition is unknown).
• Neonatal hemochromatosis (congenital alloimmune hepatitis) (OMIM 231100). Similar to TFR2-HC, neonatal hemochromatosis is associated with iron deposition in multiple organs (liver, pancreas, heart, and endocrine glands). Distinguishing features of neonatal hemochromatosis include alloimmune pathogenesis and prenatal onset (i.e., iron overload occurs in the fetus). Severe liver failure at birth is seen in neonatal hemochromatosis and the disorder is often fatal without liver transplant.

Secondary Iron Overload Disorders

Secondary iron overload disorders include iron excess resulting from different conditions. The most severe disorders result from transfusions for chronic anemia such as beta-thalassemia or sickle cell disease. Secondary iron overload may result from ingested iron in foods, cookware, and medicines, as well as parenteral iron from iron injections.

This group also includes a range of liver diseases associated with parenchymal liver disease (e.g., alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasia, familial porphyria cutanea tarda), metabolic dysfunction such as dysmetabolic iron overload syndrome, and inflammatory disorders such as rheumatoid arthritis or lupus erythematosus (of note, inflammatory disorders are not true iron overload disorders but are categorized in this group because hepcidin excess induced by inflammatory cytokines leads to the sequestration of iron in macrophages and other reticuloendothelial cells).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TFR2-HC, the evaluations summarized in Table 3 are recommended (based on recommendations for HFE-HC) [Kowdley et al 2019, European Association for the Study of the Liver 2022], if not performed as part of the evaluation that led to the diagnosis.

Treatment of Manifestations

Individuals with increased serum ferritin concentration should be treated by the same protocol as for HFE-HC, and the following recommendations are mainly based on guidelines proposed for HFE-HC in Europe [European Association for the Study of the Liver 2022] and North America [Kowdley et al 2019]. However, since TFR2-HC may progress differently from HFE-HC, individualized treatment should be provided.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for HFE-HC in Europe [European Association for the Study of the Liver 2022 ] and North America [Kowdley et al 2019].

Agents/Circumstances to Avoid

Avoid the following:

• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption, even in small amounts.
• Vitamin C supplements, which may enhance iron absorption
• Uncooked seafood, which carry a risk of infection from microorganisms thriving under conditions of excess iron (e.g., Yersinia enterocolitica, Vibrio vulnificus)
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the familial TFR2 pathogenic variants in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

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

Pregnancy Management

In pregnant women with mild-to-moderate iron overload, phlebotomy can be paused because fetal utilization of maternal iron effectively reduces the mother's iron load during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

TFR2-related hemochromatosis (TFR2-HC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a TFR2 pathogenic variant. (Note: Due to the rarity of TFR2-HC, parental consanguinity is a possible consideration if the proband has homozygous TFR2 pathogenic variants.)
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TFR2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing TFR2-HC [Joshi et al 2015].

Sibs of a proband

• If both parents are known to be heterozygous for a TFR2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing TFR2-HC [Joshi et al 2015].

Offspring of a proband. The offspring of an individual with TFR2-HC are obligate heterozygotes (carriers) for a pathogenic variant in TFR2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TFR2 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the TFR2 pathogenic variants in the family.

Note: Carrier detection using biochemical testing is not possible because iron parameters are normal in heterozygotes.

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 and discussion of the availability of prenatal/preimplantation genetic 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.
• It is appropriate to offer TFR2 molecular genetic testing for reproductive partners of individuals known to have TFR2-HC or to be heterozygous for a TFR2 pathogenic variant, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the TFR2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Iron homeostasis is regulated by the hepcidin pathway. The hepatic peptide hepcidin (encoded by HAMP) is a circulating hormone that regulates the absorption of dietary iron from the duodenum. Hepcidin expression is inappropriately decreased in hemochromatosis and is abnormally increased in the anemia of chronic diseases. Hepatic proteins essential for normal iron homeostasis, including hereditary hemochromatosis protein (encoded by HFE), transferrin receptor protein 2 (TfR2, encoded by TFR2), and hemojuvelin, function at least in part by modulating the expression of hepcidin [Colucci et al 2021]. Low/absent levels of urinary hepcidin have been reported in TFR2-related hemochromatosis (TFR2-HC) [Nemeth et al 2005], suggesting a mechanism for TFR2-HC.

TfR2 is expressed in the liver, especially in hepatocytes. TfR2 is also expressed in erythroid cells and interacts with the erythropoietin receptor [Forejtnikovà et al 2010]. TfR2 binds and internalizes transferrin. However, binding occurs at low affinity (25- to 30-fold lower) [Kawabata et al 1999], as compared to that of the transferrin receptor protein 1 (encoded by TFRC). TFR2 is not transcriptionally regulated by iron. According to the most recent in vitro models, TfR2 is able to bind hereditary hemochromatosis protein and hemojuvelin on the cell surface [Hentze et al 2010, D'Alessio et al 2012] to regulate hepcidin production. Significant expression of TfR2 has been identified outside of the liver, and in a Tfr2 knockout mouse model, local impairment of iron metabolism was found, for example, in brain and reticuloendothelial cells [Roetto et al 2018].

Mechanism of disease causation. Loss of function

Author Notes

Prof Marco De Gobbi
Web page: www.clinbio.unito.it

Dr Antonella Roetto
Web page: www.clinbio.unito.it

Prof Marco De Gobbi ([email protected]) is actively involved in clinical research regarding individuals with TFR2-related hemochromatosis (TFR2-HC). He would be happy to communicate with persons who have any questions regarding diagnosis of TFR2-HC or other considerations.

Contact Dr Antonella Roetto ([email protected]) to inquire about review of TFR2 variants.

Author History

Clara Camaschella, MD; Istituto Scientifico San Raffaele (2005-2018)
Marco De Gobbi, MD (2018-present)
Antonella Roetto, PhD (2005-present)

Revision History

• 7 December 2023 (sw) Comprehensive update posted live
• 15 February 2018 (sw) Comprehensive update posted live
• 9 June 2011 (me) Comprehensive update posted live
• 15 May 2008 (me) Comprehensive update posted live
• 29 August 2005 (me) Review posted live
• 1 February 2005 (ar) Original submission

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