Clinical Guidance

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.845GA) and p.His63Asp and homozygosity for the TFR2 pathogenic variant produced a phenotype of juvenile hemochromatosis in a single family . 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 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) .

Source: GeneReviews — "TFR2-Related Hemochromatosis"

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 . The youngest individual is a child with Alagille syndrome and homozygous for TFR2 pathogenic variant diagnosed with iron overload at age two years . In a family reported by , one middle-aged female homozygous for TFR2 pathogenic variant had iron deficiency and a history of low dietary iron intake and hypermenorrhea. also found iron deficiency in a young female homozygous for who had a history of anorexia and Helicobacter pylori-related chronic gastritis.

Source: GeneReviews — "TFR2-Related Hemochromatosis"

Diagnostic Criteria

An algorithm for the diagnosis of TFR2-related hemochromatosis (TFR2-HC) has been developed . See also , , , , and .

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

Source: GeneReviews — "TFR2-Related Hemochromatosis"

Differential Diagnosis

TFR2-related hemochromatosis (TFR2-HC) needs to be distinguished from other primary iron overload disorders as well as from secondary iron overload disorders .

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

Table 2.

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

Gene(s) | Disorder | MOI | Features of Disorder

Overlapping w/TFR2-HC | Distinguishing from TFR2-HC

BMP6 | BMP6-related iron overload (OMIM 620121) | AD | • Biochemical features of iron overload

• Liver iron accumulation

Source: GeneReviews — "TFR2-Related Hemochromatosis"

Management Guidelines

No clinical practice guidelines for TFR2-related hemochromatosis (TFR2-HC) have been published. Management and treatment follow the guidelines established for HFE-related hemochromatosis (HFE-HC).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TFR2-HC, the evaluations summarized in are recommended (based on recommendations for HFE-HC) , if not performed as part of the evaluation that led to the diagnosis.

Table 3.

TFR2-Related Hemochromatosis: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Biochemical iron parameters

| Serum iron, serum transferrin, transferrin saturation, serum ferritin |

Liver disease

| Biochemical profile of liver function: AST, ALT, ALP, bilirubin, albumin |

Liver biopsy for eval of abnormal liver function tests establishing prognosis | In those w/serum ferritin 1,000 ng/mL, esp if there is underlying liver disease (e.g., alcohol abuse, viral hepatitis)

Liver elastography to assess for hepatic fibrosis |

Endocrine

| Serum gonadotropins (FSH LH) to assess pituitary function | • At time of identification of iron overload

• If LH /or FSH are low, a GnRH stimulation test may be necessary.

Serum testosterone to assess testicular function serum estradiol to assess ovarian function | At time of identification of iron overload

• Fasting serum glucose

• Oral glucose tolerance test

| At time of identification of iron overload to assess for diabetes mellitus

Cardiac

| Cardiac eva...

Source: GeneReviews — "TFR2-Related Hemochromatosis"

Clinical Guidance

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

Source: GeneReviews — "TFR2-Related Hemochromatosis"

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.

Source: GeneReviews — "TFR2-Related Hemochromatosis"

Surveillance Guidelines

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 and North America . Table 5. TFR2-Related Hemochromatosis: Recommended Surveillance

Source: GeneReviews — "TFR2-Related Hemochromatosis"