Clinical Guidance

HAMP- and HJV-related hemochromatosis (HC) are characterized by early-onset severe iron overload. Individuals with HAMP- or HJV-related HC are rarely diagnosed before significant iron overload occurs. Reports of children with HAMP- or HJV-related HC presenting with severe iron overload stresses the importance of early diagnosis and treatment to avoid the development of organ damage, thus reducing morbidity and mortality . Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, diabetes and glucose intolerance, arthropathy, and liver fibrosis or cirrhosis. To date, approximately 160 individuals have been identified with HAMP- or HJV-related HC [, , , ]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. HAMP- and HJV-Related Hemochromatosis: Frequency of Select Features

Source: GeneReviews — "HAMP- and HJV-Related Hemochromatosis"

Differential Diagnosis

Iron overload phenotypes can be primary or secondary. Note: Iron overload disorders presenting with hyperferritinemia with normal or reduced transferrin saturation (e.g., aceruloplasminemia and ferroportin disease) and disorders with hyperferritinemia without iron overload (e.g., hyperferritinemia-cataract syndrome and benign hyperferritinemia) should not be considered in a differential diagnosis with HAMP- or HJV-related hemochromatosis (HC) because HAMP- or HJV-related HC is strongly characterized by high or very high transferrin saturation, high serum ferritin, and prevalent iron accumulation in parenchymal cells . Primary Iron Overload Disorders Although juvenile HC is most often due to pathogenic variants in HJV or HAMP, more recent studies have highlighted some age overlap at diagnosis between the various molecular subtypes of HC . Thus, absence of biallelic HAMP or HJV pathogenic variants does not rule out a diagnosis of juvenile HC in individuals with features suggestive of juvenile HC. Table 3. HAMP- and HJV-Related Hemochromatosis: Primary Iron Overload-Related Disorders with High Transferrin Saturation and Serum Ferritin to Consider in the Differential Diagnosis

Source: GeneReviews — "HAMP- and HJV-Related Hemochromatosis"

Clinical Guidance

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

Source: GeneReviews — "HAMP- and HJV-Related Hemochromatosis"

Therapies Under Investigation

At present no clinical trials are exclusively investigating HAMP- or HJV-related HC. However, several therapeutic strategies are under development that aim to restore hepcidin activity or to reduce iron absorption and efflux. Ongoing clinical and preclinical studies (including hepcidin mimetics, synthetic hepcidin, ferroportin inhibitors, and gene editing approaches) are currently focused on HFE-related HC (NCT03395704). Nevertheless, these strategies may be relevant for HAMP- and HJV-relate HC, since the underlying pathogenic mechanism is a deficient/absent production of hepcidin or its regulatory pathways. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "HAMP- and HJV-Related Hemochromatosis"