Tfr2-Related Hereditary Hemochromatosis

Watchlist

(log in to enable)

Retrieved

2021-01-18

Source

GeneReviews

Trials

—

Genes

—

Drugs

—

Interested in hearing about new therapies?

Summary

Clinical characteristics.

TFR2-related hereditary hemochromatosis (TFR2-HHC) 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-associated HHC. 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, 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, and arthropathy.

Diagnosis/testing.

The diagnosis of TFR2-HHC is established in a proband by identification of biallelic pathogenic variants in TFR2 on molecular genetic testing.

Management.

Treatment of manifestations: Removal of excess iron by routine phlebotomy to maintain serum ferritin concentration at 50 ng/mL or lower and transferrin-iron saturation below 50%; lifelong hormone replacement therapy for hypogonadism; gonadotropins for fertility/pregnancy; nonsteroidal anti-inflammatory drugs and joint replacement for arthropathy; routine treatment for cardiac failure, diabetes mellitus, and hepatic complications.

Prevention of primary manifestations: Routine phlebotomy; see Treatment of manifestations.

Surveillance: Monitoring serum ferritin concentration every three to four months once serum ferritin concentration is lower than 50 ng/mL.

Agents/circumstances to avoid: Medicinal iron and nutritional supplements containing iron, excessive alcohol intake, vitamin C supplements, uncooked seafood.

Evaluation of relatives at risk: If the pathogenic variants in the family are known, molecular genetic testing of at-risk relatives to allow early diagnosis and treatment.

Genetic counseling.

TFR2-HHC 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 asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and do not have abnormalities of iron parameters. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once both pathogenic variants in the family have been identified.

Diagnosis

An algorithm for the diagnosis of TFR2-related hereditary hemochromatosis (TFR2-HHC) has been developed (see Figure 1). See also Bardou-Jacquet et al [2013], Brissot [2016], Powell et al [2016], and Zoller & Henninger [2016].

Figure 1.

Flowchart for diagnosis of TFR2-HCC

Suggestive Findings

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

Clinical features and symptoms of iron overload

Weakness, chronic fatigue
Abdominal pain
Hepatomegaly
Cirrhosis, hepatocellular carcinoma
Diabetes mellitus
Cardiomyopathy, ECG abnormalities (conduction disturbances)
Hypogonadism (decreased libido and impotence in men, amenorrhea in women)
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-HHC [Girelli et al 2002, Pietrangelo et al 2005, Hsiao et al 2007, Pelucchi et al 2009, Del Castillo-Rueda et al 2011, Hattori et al 2012, Joshi et al 2015, Badar et al 2016, Peters at al 2017]. 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 developed to quantitate liver iron concentration have been applied to TFR2-HHC [Biasiotto et al 2008, Pelucchi et al 2009, Ricerca et al 2009, Del Castillo-Rueda et al 2011, Del-Castillo-Rueda et al 2012, Joshi et al 2015, Badar et al 2016].

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

Establishing the Diagnosis

No specific diagnostic guidelines are available for TFR2-HHC.

The diagnosis of TFR2-HHC is established in a proband by identification of biallelic pathogenic variants in TFR2 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

Single-gene testing. Sequence analysis of TFR2 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
A multigene panel that includes TFR2 and other genes of interest (see Differential Diagnosis) can be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in TFR2-Related Hereditary Hemochromatosis

Gene ¹	Test Method	Proportion of Pathogenic Variants ² Detectable by This Method
TFR2	Sequence analysis ³	>99% ⁴
TFR2	Gene-targeted deletion/duplication analysis ⁵	Unknown ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: McDonald et al [2015], Badar et al [2016], Faria et al [2016], Lanktree et al [2017], Peters et al [2017]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

TFR2-related hereditary hemochromatosis (TFR2-HHC) 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-HHC is earlier than in individuals with HFE-associated hereditary hemochromatosis. Five individuals with childhood onset (range of onset: age 3-13 years) have been reported [Piperno et al 2004, Biasiotto et al 2008, Joshi et al 2015, Ravasi et al 2015], all with increased transferrin saturation and serum ferritin concentration. 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], or as adults with abnormal serum iron studies and signs of organ involvement (e.g., liver fibrosis or cirrhosis, diabetes, hypogonadism, arthropathy) [Pelucchi et al 2009, Del-Castillo-Rueda et al 2012, Hattori et al 2012, Joshi et al 2015, Badar et al 2016, Peters et al 2017, Wang et al 2017].

Disease progression is slower than in juvenile hereditary hemochromatosis [De Gobbi et al 2002].

When TFR2-HHC is progressive, complications can include cirrhosis and hypogonadotropic hypogonadism. Severe joint involvement has been reported [Ricerca et al 2009, Peters et al 2017]. Cardiomyopathy and diabetes mellitus are rare [De Gobbi et al 2002, Riva et al 2004]. While the distribution of liver iron deposition is similar to that seen in HFE-associated hereditary hemochromatosis (mainly in hepatocytes with a decreasing gradient from portal to centrolobular areas), hepatocellular carcinoma (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].

If TFR2-HHC is diagnosed early and treated appropriately with phlebotomy, individuals with TFR2-HHC will have normal life expectancy. Similar to HFE-associated hereditary hemochromatosis, the most important factors that can influence survival are the onset of cirrhosis, diabetes, and/or cardiomyopathy. The oldest individual to be diagnosed with TFR2-HHC is an Italian individual diagnosed at age 82 years [Roetto et al 2001].

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 (NP_000401.1; 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].

Penetrance

The penetrance of TFR2-HHC is less than 100% and can be influenced by environmental factors. In a family reported by Roetto et al [2001], one middle-aged female homozygous for the TFR2 p.Arg30ProfsTer31 pathogenic variant had iron defiency 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-HHC is also known as hemochromatosis type 3 (HFE3); however, the term HFE3 seems inappropriate because HFE has no role in TFR2-HHC.

Prevalence

TFR2-HHC is rare, with pathogenic allele frequencies estimated within the range of 0.000008 to 0.0002 [Wallace & Subramaniam 2016]. Approximately 50 affected individuals have been reported worldwide, most commonly in Italy, Japan, and Portugal.

In Japan, where hemochromatosis is rare and heterogeneous, it has been proposed that TFR2-HHC is the most frequent form of hereditary hemochromatosis [Hayashi et al 2006]; however, studies are limited.

Differential Diagnosis

TFR2-related hereditary hemochromatosis (TFR2-HHC) needs to be distinguished from other primary iron overload disorders as well as from secondary iron overload disorders (see Figure 1). No specific studies have evaluated the percentage of TFR2 pathogenic variants detected in individuals with non-HFE-associated hereditary hemochromatosis.

Primary Iron Overload Disorders

Table 2.

Primary Iron Overload Disorders to Consider in the Differential Diagnosis of TFR2-HHC

Disorder ¹	Gene(s)	MOI	Clinical Features of This Disorder
Disorder ¹	Gene(s)	MOI	Overlapping with TFR2-HHC	Distinguishing from TRF2-HHC
HFE-related hereditary hemochromatosis	HFE	AR	Biochemical & clinical features of iron overload	Lower penetrance Later onset
Juvenile hereditary hemochromatosis	HJV HAMP	AR	Biochemical & clinical features of iron overload	Full penetrance Earlier onset More severe clinical manifestations, esp cardiomyopathy & hypogonadism
Ferroportin 1-associated hemochromatosis (OMIM 606069)	SLC40A1	AD	Biochemical & clinical features of iron overload	Later-onset clinical manifestations of iron overload
Ferroportin disease ²	SLC40A1	AD	Hyperferritinemia	At early stage: anemia & low transferrin saturation Iron deposition in hepatic reticuloendothelial (not parenchymal) cells Reduced tolerance to phlebotomy
Aceruloplasminemia	CP	AR	Hyperferritinemia Diabetes mellitus	Anemia Iron deposition in hepatic reticuloendothelial (not parenchymal) cells Brain iron accumulation manifesting as retinal degeneration & neurologic disease (movement disorders & ataxia)
African iron overload (OMIM 601195)	Unknown		Liver iron accumulation in reticuloendothelial & parenchymal cells Cirrhosis	In drinkers of beer brewed in non-galvanized steel drums Lower frequency of cardiomyopathy & diabetes Susceptibility to tuberculosis & other infections
Neonatal hemochromatosis (congenital alloimmune hepatitis) (OMIM 231100)	Unknown		Iron deposition in multiple organs (liver, pancreas, heart, endocrine glands)	Alloimmune pathogenesis Iron overload in fetus Severe liver failure at birth, often fatal without liver transplant
Bmp6-related iron overload (OMIM 112266)	BMP6	AD	Biochemical features of iron overload Liver iron accumulation	Normal transferrin saturation in some Mild-to-moderate late onset of iron overload

: AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
1.: Primary overload disorders are characterized by increased absorption of iron from a normal diet.
2.: Pietrangelo [2017]

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, porphyria cutanea tarda) and inflammatory disorders such as rheumatoid arthritis (which are questionable because inflammatory disorders are not true iron-loading disorders).

See Hemochromatosis: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TFR2-related hereditary hemochromatosis (TFR2-HHC), the following are recommended (based on recommendations for HFE-associated hereditary hemochromatosis) if they have not already been completed:

Liver biopsy for evaluation of abnormal liver function tests and establishing prognosis when serum ferritin concentration is greater than 1,000 ng/mL, especially if there is an underlying liver disease (e.g., alcohol abuse, viral hepatitis)
Liver elastography for detecting hepatic fibrosis
Serum concentration of gonadotropins (FSH and LH) to assess pituitary function at time of diagnosis of iron overload. Depending on the results, a GnRH stimulation test may be necessary.
Serum concentration of testosterone to assess testicular function and serum concentration of estradiol to assess ovarian function at time of diagnosis of iron overload
Radiographs of the affected joint(s) to assess persistent arthralgia or arthropathy
Cardiac evaluation (ECG and echocardiography) for all symptomatic individuals and those with severe iron overload (ferritin >1,000 ng/mL)
Screening for diabetes mellitus by fasting serum glucose concentration and oral glucose tolerance test at time of diagnosis of iron overload
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Since individuals with increased serum ferritin concentration should be treated by the same protocol as for HFE-associated hereditary hemochromatosis, the following recommendations are mainly based on guidelines proposed for HFE-associated hereditary hemochromatosis in Europe [European Association for the Study of the Liver 2010] (full text) and North America [Bacon et al 2011] (full text). However, it should be emphasized that since TFR2-HHC is rare and may progress differently from HFE-associated hemochromatosis, individual treatment is important.

Therapeutic Phlebotomy

Periodic phlebotomy (i.e., removal of a unit of blood) is a simple, inexpensive, safe, and effective way to remove excess iron. Each unit of blood (400-500 mL) with a hematocrit of 40% contains approximately 160-200 mg of iron.

The usual therapy is phlebotomy weekly or every two weeks; however, twice-weekly phlebotomy or erythrocytapheresis may be useful initially to accelerate iron depletion. Hematocrit or hemoglobin level should be checked prior to each phlebotomy. In the initial stage of treatment, when serum ferritin is high, ferritin measurement should be performed approximately every ten phlebotomies.

Weekly phlebotomy is carried out until the serum ferritin concentration is 50 ng/mL or lower. If anemia is detected or hematocrit is reduced from the initial level by more than 20%, phlebotomy should be postponed.

As the target range of 50-100 ng/mL is approached, serum ferritin analysis may be repeated more frequently.

Note: Although experience is limited because of the small number of affected individuals identified worldwide, it should be noted that transferrin saturation remains high in TFR2-related hereditary hemochromatosis when serum ferritin concentration is low (<50 ng/mL), even after intensive phlebotomy [Girelli et al 2011; Camaschella, Roetto, & De Gobbi, unpublished observations].

Maintenance therapy. The goal is to maintain serum ferritin concentration around 50 ng/mL and transferrin-iron saturation below 50%. Phlebotomy to prevent reaccumulation of iron is performed about every three to four months. However, the frequency of maintenance therapy varies by individual.

Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia or cardiac dysfunction that makes therapeutic phlebotomy impossible. Subcutaneous desferrioxamine has been used in individuals with concomitant anemia alone [Riva et al 2004] or in combination with deferiprone [Tauchenová et al 2016]. A Phase I/II trial with the oral chelator deferasirox demonstrated that this treatment is feasible, safe, and effective – although associated with a high incidence of gastrointestinal side effects [Phatak et al 2010].

Treatment of Clinical Complications

Cirrhosis should be treated and followed up as in other conditions. Although cirrhosis is not reversible by phlebotomy, individuals with cirrhosis benefit from iron removal in that it reduces the risk of hepatocellular cancer.

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.

Arthropathy requires nonsteroidal anti-inflammatory drugs and is barely influenced by phlebotomy. In some individuals, joint replacement has been performed.

Cardiac failure is treated with diuretics, ACE inhibitors, cardiac glycosides, and iron chelation by intravenous or subcutaneous desferrioxamine.

Diabetes mellitus may require lifelong insulin treatment. Iron removal may improve control of diabetes mellitus but cannot reestablish normal glucose metabolism.

Prevention of Primary Manifestations

In affected individuals with increased serum ferritin concentration, prevention of primary manifestations is accomplished by weekly phlebotomy to deplete iron stores (see Treatment of Manifestations).

Surveillance

As with treatment, the surveillance of TFR2-HHC is based on guidelines proposed for HFE-associated hereditary hemochromatosis in Europe [European Association for the Study of the Liver 2010] (full text) and North America [Bacon et al 2011] (full text).

Once the serum ferritin concentration is around 50 ng/mL, monitoring serum ferritin concentration every three to four months is adequate while continuing phlebotomies at intervals to keep ferritin at this level.

Although hepatocellular carcinoma has not been reported in individuals with TFR2-associated hereditary hemochromatosis, surveillance for its development should be performed in persons with cirrhosis by monitoring liver ultrasound examinations and serum concentrations of alpha-fetoprotein, as in persons with cirrhosis with HFE-associated hereditary hemochromatosis.

Agents/Circumstances to Avoid

Avoid the following:

Medicinal iron and nutritional supplements containing iron
Excessive alcohol intake because it increases iron absorption and is toxic to the hepatocytes
Vitamin C supplements because they may enhance iron absorption
Uncooked seafood because of the risk of infection from microorganisms thriving under conditions of excess iron (e.g., Yersinia enterocolitica, Vibrio vulnificus)

Evaluation of Relatives at Risk

In order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures, 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.

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

Pregnancy Management

Women with hemochromatosis do not need treatment during pregnancy 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.