Table 3.

Primary Iron Overload-Related Disorders with High Transferrin Saturation and Serum Ferritin to Consider in the Differential Diagnosis of Juvenile Hemochromatosis

GeneDifferential Diagnosis DisorderMOIFeatures of Differential Diagnosis Disorder
Overlapping w/JHDistinguishing from JH
HFE HFE hemochromatosis AR
  • Iron overload distribution mainly involving parenchymal cell; sparing reticuloendothelial macrophages
  • Hepatic fibrosis/cirrhosis
  • Diabetes mellitus
  • Skin hyperpigmentation
  • Cardiomyopathy
  • Hypogonadotropic hypogonadism
  • Transferrin saturation less ↑ (variably ranges >45%)
  • Low penetrance w/variable expression
  • Later onset (40s-50s)
  • Hepatic fibrosis/cirrhosis more common
  • Hepatocellular carcinoma most frequent cause of death
  • Cardiomyopathy & hypogonadism less common
TFR2 TFR2 hereditary hemochromatosis AR
  • Transferrin saturation in TFR2-HHC often as ↑ as in JH 1
  • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages
  • Hepatic fibrosis/cirrhosis
  • Diabetes mellitus
  • Skin hyperpigmentation
  • Cardiomyopathy
  • Hypogonadotropic hypogonadism
  • Cardiomyopathy & hypogonadism less common
  • Phenotype (age of onset & complications) intermediate between HFE-HHC & HJV-JH related to age of presentation & clinical complications 2
SLC40A1 Type 4 hemochromatosis 3, 4
(OMIM 606069)		AD
  • Iron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages
  • Hepatic fibrosis/cirrhosis
  • Diabetes mellitus
  • Skin hyperpigmentation
  • Cardiomyopathy (less than in JH)
  • Hypogonadotropic hypogonadism (less than in JH)
  • Typically presents in 40s & 50s (vs <30 yrs in JH)
  • Because of lower rate of iron accumulation, clinical findings (esp hypogonadism & cardiomyopathy) less common than in JH
  • Note: It is generally assumed that type 4 HHC is similar to HFE-HHC in age of presentation & clinical complications
TF Atransferrinemia 5
(OMIM 209300)		ARIron overload distribution mainly involving parenchymal cells; sparing reticuloendothelial macrophages
  • Ultra-rare; <15 individuals
  • Age of presentation: 1-2 yrs
  • Severe microcytic anemia that may require blood transfusion
  • Undetectable serum transferrin & very ↓ serum iron levels
  • If untreated, growth deficiency, severe iron-related complications & death may occur.
SLC11A2 DMT1 deficiency 6
(OMIM 206100)		ARVariably ↑ serum ferritin that is disproportionally ↓ compared to liver iron concentration
  • Ultra-rare, <10 individuals
  • Age of presentation: postnatal to young adult
  • Severe microcytic anemia that may require blood transfusion
  • If untreated, growth deficiency may occur.

AD = autosomal dominant; AR = autosomal recessive; DMT1 = divalent metal transporter; HHC = hemochromatosis; JH = juvenile hemochromatosis; MOI = mode of inheritance

1.

Some TFR2 pathogenic variants can cause juvenile-like hemochromatosis and increased iron indices in childhood [Le Gac et al 2004, Ravasi et al 2015].

2.
3.

Mutation of SLC40A1 can lead to two different disorders of iron metabolism, previously classified as hemochromatosis type-4A and type-4B. The former and most frequent, type-4A, is characterized by atypical manifestations that do not correspond to hemochromatosis. Owing to this, it should be considered a distinct disorder characterized by hyperferritinemia with normal transferrin saturation and prevalent iron accumulation in macrophages (ferroportin disease). Type-4B shows typical serum iron index alterations and pattern of iron overload and should be now referred to as type 4 hemochromatosis [Pietrangelo 2017, Brissot et al 2018, Viveiros et al 2019]. Type 4 hemochromatosis is caused by gain-of-function variants that affect amino acids interacting with hepcidin, resulting in complete or partial resistance to hepcidin (see Molecular Pathogenesis).

4.

Because of the rarity of type 4 hemochromatosis, data should be interpreted with caution.

5.

In atransferrinemia, the lack of serum transferrin causes the loss of its iron scavenger and transport functions leading to severe iron deficiency anemia, non-transferrin-bound iron formation and severe iron overload in non-hematopoietic tissues.

6.

DMT1 deficiency is also referred to as hypochromic microcytic anemia with iron overload-1. DMT1 transmembrane protein is involved in dietary non-heme iron uptake and plays a crucial role in iron utilization at the endosomal membrane of the erythroid precursors. In humans, DMT1 has a prevalent role in erythroid cells, and the reduction of DMT1 causes a more complex phenotype characterized by congenital microcytic anemia (due to defective iron transport and utilization in erythroid precursors) and biochemical and histologic features of iron overload [Iolascon & De Falco 2009].

From: Juvenile Hemochromatosis

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