At what age does genetic screening for hereditary hemochromatosis (HH) typically start?

Genetic Screening Age for Hereditary Hemochromatosis

Genetic testing for hereditary hemochromatosis should be offered after 18 years of age to first-degree relatives of patients with confirmed hemochromatosis. 1

Screening Approach by Population

First-Degree Relatives of Confirmed Cases

• Genetic testing (HFE mutation analysis) combined with iron studies (transferrin saturation and serum ferritin) should be performed after age 18 years in first-degree relatives of patients with confirmed hereditary hemochromatosis 1, 2
• This represents the primary target population for genetic screening, as family-based screening identifies individuals at highest risk before clinical manifestations develop 3

General Population Screening

• Population-wide genetic screening is NOT recommended by the U.S. Preventive Services Task Force due to low clinical penetrance (fewer than 10% of C282Y homozygotes develop full clinical disease), uncertain benefit of early treatment in asymptomatic genotype-positive individuals, and potential for false positives 4, 5
• The optimal age for early treatment remains uncertain, and systematic screening is potentially costly with ethical concerns about genetic testing when disease prediction is uncertain 3

Targeted Case-Finding in Adults

• For symptomatic adults or those with abnormal iron studies, genetic testing should be performed regardless of age when transferrin saturation ≥45% and/or elevated serum ferritin (>300 μg/L in men, >200 μg/L in women) is documented 4
• Targeted screening is appropriate for adults with unexplained liver disease, type 2 diabetes with hepatomegaly, early-onset arthropathy, cardiac disease, or male sexual dysfunction 5

Age-Related Clinical Considerations

Why Age 18 for Family Screening?

• Clinical disease typically manifests in the 40s or 50s, with women diagnosed later than men due to protective effects of menstrual blood loss 1, 6
• The disease evolves in stages: clinically insignificant iron accumulation (0-20 years), iron overload without disease (20-40 years), and iron overload with organ damage (usually >40 years with >20g parenchymal iron storage) 3
• Testing after age 18 allows for informed consent while still enabling intervention before the typical age of organ damage 1

Gender-Specific Timing

• Males aged 30 years and females aged 45 years represent the populations studied for screening in northern European ancestry populations, reflecting the later clinical presentation in women 3
• Women typically begin presenting clinically in the fifth decade of life, as menstrual blood loss provides protection against iron accumulation until menopause 3, 7

Critical Pitfalls to Avoid

• Do not screen children under 18 years unless there are compelling clinical symptoms, as genetic testing raises ethical concerns about insurability and psychological impact of disease labeling in minors 3, 4
• Do not rely on genetic testing alone - always combine with phenotypic assessment (transferrin saturation and serum ferritin) as genetic mutations have incomplete penetrance 3, 2
• Recognize that C282Y homozygosity does not guarantee clinical disease - only 58% develop progressive tissue iron overload despite 100% having elevated transferrin saturation 3
• Before genetic testing, exclude secondary causes of elevated ferritin including chronic alcohol consumption, inflammatory conditions, malignancy, and metabolic syndrome 4