Clinical characteristics.

Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, glucose intolerance and diabetes, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has been reported occasionally. The main cause of death is cardiac disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.

Diagnosis/testing.

The diagnosis of juvenile hemochromatosis is established in a proband with clinical and laboratory features of iron overload by identification of biallelic pathogenic variants in HAMP or HJV on molecular genetic testing. Individuals with suggestive features of juvenile hemochromatosis who do not have biallelic HAMP or HJV pathogenic variants identified on molecular genetic testing should have further evaluation by imaging and/or liver biopsy.

Management.

Treatment of manifestations: Phlebotomy for treatment of iron overload as for HFE hemochromatosis: phlebotomy of 1 unit of blood (~200 mg of iron) 1x/week for up to 2-3 years to reduce iron stores to desired levels (serum ferritin concentration ~50 ng/mL), followed by phlebotomies to maintain normal serum iron levels. Conventional treatment of secondary complications including hypogonadotropic hypogonadism, arthropathy, cardiac failure, liver disease, and diabetes mellitus as indicated. Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Arthropathy is treated with analgesics and NSAIDs. Cardiac failure and arrhythmias require treatment as per cardiologist. Glucose intolerance or diabetes may require oral agents or insulin administration.

Prevention of primary manifestations: Individuals with biochemical evidence of iron overload but without evidence of organ dysfunction or failure should be encouraged to undergo regular phlebotomies until excess iron stores are depleted to prevent the development of complications associated with excess iron stores.

Prevention of secondary complications: Hormone replacement therapy may prevent osteoporosis.

Surveillance: Monitor those at risk with annual measurement of serum ferritin concentration and transferrin saturation starting in early childhood. For individuals with iron overload: serum ferritin every 4-8 phlebotomies during the induction phase; every 1-2 phlebotomies as ferritin levels approach the target of 50 ng/mL; liver function tests and fibroelastography every 6-24 months according to severity of liver dysfunction; abdominal ultrasound and serum alpha-fetoprotein concentration every 6 months in those with severe fibrosis or cirrhosis to monitor for hepatocellular cancer; cardiac ultrasound and MR-based quantitation of iron according to the severity of cardiac dysfunction; Holter ECG as needed to evaluate for arrhythmias; serum FSH, LH, and testosterone or estradiol every 12 months or as needed; fasting and postprandial serum glucose and Hgb A1c every 6-12 months according to needs; vitamin D, PTH, serum and urinary calcium and phosphorus, C-terminal telopeptide every 12 months according to needs; DEXA every 24 months or as needed.

Agents/circumstances to avoid: Alcohol consumption; ingestion of iron-containing preparations and supplemental vitamin C; handling or eating uncooked shellfish or marine fish because of risk of fatal septicemia from the marine bacterium V vulnificus.

Evaluation of relatives at risk: It is appropriate to clarify the clinical/genetic status of all at-risk family members (i.e., sibs) of an affected individual in order to identify as early as possible those who would benefit from early monitoring for the development of iron overload. If juvenile hemochromatosis is detected before evidence of organ damage, treatment via phlebotomy can reverse or prevent many of the secondary complications resulting from organ damage. Evaluation can include serum iron indices (i.e., serum iron, transferrin saturation, and serum ferritin), serum transaminases, C-reactive protein, and molecular genetic testing in relatives at risk before evidence of organ damage from iron overload.

Genetic counseling.

Juvenile hemochromatosis is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a HAMP or HJV pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing are possible if both pathogenic variants in the family have been identified.

Suggestive Findings

Juvenile hemochromatosis should be suspected in individuals with the following findings:

• Less specific symptoms in the first decade (e.g., fatigue, arthralgia, lack of appetite), which are often erroneously attributed to iron deficiency anemia
• Decreased libido, impotence (males), and amenorrhea (females) in adolescents and/or young adults suggesting hypogonadotropic hypogonadism
• Hepatomegaly, slight alterations of serum transaminases suggesting liver disease or severe fibrosis/cirrhosis
• Fasting hyperglycemia, glucose intolerance, or frank diabetes
• Arrhythmias, dyspnea on exertion, heart failure suggesting cardiomyopathy
• Arthropathy and osteoporosis
• Hyperpigmentation

Note: Many of these features are evident before age 30 years, although they may appear at a later age in some individuals [Kong et al 2019].

Laboratory features

• Transferrin saturation, which is typically high, often reaching 100% (normal values 16%-45%). Normal transferrin saturation excludes the diagnosis of juvenile hemochromatosis.
• Serum ferritin concentration, which is increased relative to the normal values for age and gender according to data published by the World Health Organization:
  • Upper normal value in male and female children and young adolescents: 100-125 ng/mL
  • Upper normal value in premenopausal adult women: 150 ng/mL, and in postmenopausal women: 250 ng/mL [Milman et al 2003]
  • Upper normal value in healthy adult men: 400 ng/mL [Milman et al 2002]
  • In the earlier stages of juvenile hemochromatosis, serum ferritin can be slightly increased, but can rapidly increase over 1000 ng/mL and even much higher.

Establishing the Diagnosis

The diagnosis of juvenile hemochromatosis is established in a proband by identification of biallelic pathogenic variants in HAMP or HJV on molecular genetic testing (see Table 1) [Piperno 2013, Porto et al 2016, Brissot et al 2018].

Molecular genetic testing approaches can include use of a multigene panel or single-gene testing:

• An iron overload multigene panel that includes HAMP, HJV, HFE, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost, including digenic forms of hemochromatosis and genetic variants in modifier genes [Badar et al 2016, Faria et al 2016, Wallace & Subramaniam 2016]. 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. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing can be considered in individuals with early-onset iron overload. Sequence analysis of HJV can be performed first to detect small indels and missense, nonsense, and splice site variants. If no or only one pathogenic variant is found, perform sequence analysis of HAMP. If no or only one pathogenic variant is identified, consider other genes of interest (see Differential Diagnosis). If no or only one pathogenic variant is identified, perform gene-targeted deletion/duplication analysis of HAMP, HJV, and other genes of interest (see Differential Diagnosis) to detect intragenic deletions or duplications.

Clinical Description

To date, approximately 120 individuals have been identified with juvenile hemochromatosis [De Gobbi et al 2002, Merryweather-Clarke et al 2003, Roetto et al 2003, Delatycki et al 2004, Jacolot et al 2004, Matthes et al 2004, Roetto et al 2004, Island et al 2009, Lok et al 2009, Hattori et al 2012, Kong et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Juvenile hemochromatosis is characterized by early-onset severe iron overload. Individuals with juvenile hemochromatosis typically present in the first to third decade of life; however, adult presentation has been described in individuals with HJV hemochromatosis [Koyama et al 2005, Ravasi et al 2018, Kong et al 2019], expanding the spectrum of disease phenotypes related to HJV pathogenic variants from classic juvenile hemochromatosis at one extreme to a late-onset adult form at the other extreme. Males and females are equally affected.

Individuals with juvenile hemochromatosis are rarely diagnosed before significant iron overload occurs. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, diabetes and glucose intolerance, arthropathy, and liver fibrosis or cirrhosis.

Cardiac. The prevalence of cardiac disease is strikingly high [De Gobbi et al 2002, Kong et al 2019] and in some individuals is the presenting finding [Filali et al 2004]. Myocardial iron accumulation induces the development of restrictive cardiomyopathy with early diastolic dysfunction that may progress towards dilated cardiomyopathy. Heart failure is the main cause of death in untreated individuals with juvenile hemochromatosis [Murphy & Oudit 2010]. A variety of arrhythmias and sudden death can also occur in individuals with severe iron overload although further investigations to clarify the etiology and clinical relevance of iron overload-induced arrhythmias are needed [Shizukuda & Rosing 2019]. Iron removal can significantly improve and/or normalize cardiac function [Murphy & Oudit 2010].

Hypogonadotropic hypogonadism characterized by low levels of gonadotropins (FSH and LH) and testosterone is the most frequent endocrinologic complication in individuals with iron overload due to juvenile hemochromatosis [De Gobbi et al 2002, Borgna-Pignatti et al 2004]. It causes decreased libido and infertility, amenorrhea in females, and impotence in males, and contributes to the development of osteoporosis. Iron removal in early stages can lead to symptomatic improvement or resolution and normalization of hormonal indices [Angelopoulos et al 2006, Pelusi et al 2016].

Diabetes mellitus. Most of the information on diabetes development has been obtained in individuals with HFE hemochromatosis, where the pathogenesis of glucose intolerance and diabetes is likely multifactorial. Autopsy findings in individuals with hemochromatosis showed variable iron deposition in the exocrine pancreas and in beta cells together with loss of endocrine granules. It can be hypothesized that a severe and rapid iron overload in the exocrine pancreas could induce an initial beta-cell oxidative stress followed by iron accumulation and decreased insulin secretory capacity secondary to beta-cell apoptosis and desensitization of glucose-induced insulin secretion [Backe et al 2016]. Glucose intolerance or diabetes may require oral agents or insulin administration. Phlebotomy has a variable impact on diabetes control. In general, it may prevent progression if started in the earlier stages of disease, although the majority of individuals with diabetes will experience no significant change or worsening in their glucose metabolism control [Angelopoulos et al 2007, Pelusi et al 2016].

Liver. Although hepatomegaly is usually included among the earlier manifestations of juvenile hemochromatosis there is no information on its frequency as it is often poorly noted in clinical evaluations. Because the liver can compensate for iron toxicity, cirrhosis takes decades to develop. While in individuals with HFE hemochromatosis a serum ferritin value above 1000 ng/mL is a validated marker of increased risk of severe hepatic fibrosis/cirrhosis [Allen et al 2010], there are no data available for juvenile hemochromatosis. Therefore, assessment by liver fibroelastography and/or liver biopsy is mandatory. Environmental (e.g., alcohol consumption, steatosis, coexistent viral infection) and possibly genetic factors can modify the risk for cirrhosis [Brissot et al 2018]. Based on data related to other liver disease and HFE hemochromatosis [Falize et al 2006] it can be assumed that iron depletion can improve fibrosis unless cirrhosis is fully established. Hepatocellular carcinoma is rarely reported in individuals with juvenile hemochromatosis [Ramzan et al 2017]. A possible explanation is that untreated individuals with juvenile hemochromatosis die prematurely as a result of cardiac complications.

Skeletal. Articular symptoms, arthralgias, and/or arthritis was reported in seven of eight individuals with HJV hemochromatosis [Vaiopoulos et al 2003]. The age at onset of arthropathy ranged from 20 to 45 years. In two individuals arthropathy preceded other symptoms of juvenile hemochromatosis. The involved joints were most frequently metacarpophalangeal joints; knees, lumbar spine, and shoulder and metatarsophalangeal joints were variably involved. Four of the six individuals evaluated had osteopenia or osteoporosis, common complications in individuals with prolonged hypogonadism. However, a more recent study of 73 individuals with HJV hemochromatosis reported a very low frequency of osteopathy (7%) [Kong et al 2019] – a finding to be taken with caution because osteopenia and osteoporosis can be underestimated if not sought with appropriate investigations through bone densitometry (DEXA). Iron removal, in contrast with the visceral manifestations, often did not mitigate orthopedic complications [Sahinbegovic et al 2010].

Skin. A recent review reported hyperpigmentation in approximately 25% of individuals with HJV hemochromatosis [Kong et al 2019] – a finding that contrasts with older reports of skin hyperpigmentation at diagnosis in about 90% of individuals with hemochromatosis. Hyperpigmentation developed very gradually. This may suggest that iron-induced skin changes take too long to manifest in the majority of individuals with juvenile hemochromatosis.

If juvenile hemochromatosis is detected early and treated with phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.

Other. Although individuals with juvenile hemochromatosis may develop adrenocortical insufficiency or hypothyroidism, these complications are rare [Varkonyi et al 2000, Pelusi et al 2016].

Heterozygotes and digenic inheritance. Heterozygous pathogenic variants in HAMP, HJV, and/or TFR2 have been shown to increase the risk for iron overload in HFE p.Cys282Tyr heterozygotes [Merryweather-Clarke et al 2003] and to increase iron burden in HFE p.Cys282Tyr homozygotes [Jacolot et al 2004, Majore et al 2004, Pietrangelo et al 2005]. However, only a very small proportion of individuals with HFE hemochromatosis are reported to have polygenic inheritance due to pathogenic variants in HAMP and HJV.

Genotype-Phenotype Correlations

No genotype-phenotype correlations can be provided for HAMP juvenile hemochromatosis due to the small number of reported individuals.

HJV. More than 90% of homozygotes with HJV pathogenic variants in exons 2 and/or 3 developed hemochromatosis before age 30, compared with only 66% of homozygotes with HJV pathogenic variants in exon 4 [Kong et al 2019], indicating that the genetic defects in exons 2 and 3 may have a more deleterious effect on HJV function.

Nomenclature

Despite use of the locus names HFE2A and HFE2B for the two juvenile hemochromatosis genes (HJV and HAMP, respectively), juvenile hemochromatosis is not associated with pathogenic variants in HFE – mutation of which causes HFE hemochromatosis, an adult-onset disorder of iron storage.

Prevalence

Juvenile hemochromatosis is rare; global HJV pathogenic allele frequency has been estimated at 0.000316-0.00074 [Wallace & Subramaniam 2016]. Affected individuals have been reported worldwide. The variant p.Gly320Val is the most prevalent pathogenic variant (>50%) reported to date; p.Cys321Ter is the most frequent pathogenic variant in individuals of Chinese ancestry; p.Gln312Ter (also reported in individuals of Chinese ancestry) and p.Asp249His are the predominant pathogenic variants in Japan [Ikuta et al 2017]; p.Arg385Ter recurs in North Africa and Italy [Lanzara et al 2004, Kong et al 2019]. The variant p.Ala310Gly is common in African Americans and Brazilians, but its role is still undefined [Lee et al 2004, Santos et al 2011]. Table 7 reports the most frequent pathogenic variants according to ethnicity.

Primary Iron Overload Disorders

Secondary Iron Overload Disorders

Transfusional iron overload. One unit of packed red blood cells contains approximately 200–250 mg of iron. Individuals requiring frequent transfusions due to inherited anemias (e.g., thalassemia major, Diamond-Blackfan anemia) will develop severe iron overload and iron-related complications at an early age if untreated. Other transfusion-dependent iron overload conditions include survivors of bone marrow transplant, myelodysplastic disorders, myeloproliferative syndromes, and aplastic anemia. Iron accumulation occurs initially in the reticuloendothelial macrophages. After iron excess overwhelms homeostatic mechanisms in macrophages, transferrin becomes fully saturated leading to elevated non-transferrin-bound iron and parenchymal iron overload [Porter et al 2014].

Iron loading anemias. This group of disorders includes: non-transfusion-dependent thalassemia (thalassemia intermedia), congenital and acquired sideroblastic anemias, congenital dyserythropoietic anemias, pyruvate kinase deficiency, and other anemias, all characterized by ineffective erythropoiesis. Chronic anemia, hypoxia, and ineffective erythropoiesis activate erythroid signaling, suppressing liver hepcidin synthesis and leading to increased intestinal iron absorption and iron release from macrophages [Muckenthaler et al 2017]. High transferrin saturation and ferritin, and parenchymal iron overload are typical manifestations of this group of disorders.

African iron overload (OMIM 601195) occurs in individuals with a predisposition to iron overload that is exacerbated by excessive intake of dietary iron. Iron accumulation primarily involves reticuloendothelial macrophages and later hepatocytes. It is particularly prevalent among Africans who drink a traditional beer brewed in non-galvanized steel drums. However, serious iron overload does not develop in all beer drinkers, and not all individuals with iron overload consume excessive amounts of the beer, suggesting that other yet-to-be defined iron-related genes predispose to the condition. SCL40A1 pathogenic variant p.Gln284His appeared to be unique to African populations and associated with a mild iron-loading tendency [Gordeuk et al 2003]. However, a subsequent study failed to show that p.Gln284His was responsible for iron overload, while it could influence the inflammatory response in African populations [McNamara et al 2005].

Neonatal hemochromatosis (NH) is a severe liver disorder associated with extrahepatic siderosis with the same distribution seen in juvenile hemochromatosis (sparing the reticulo-endothelial system). NH is characterized by high mortality. Recurrence is approximately 80% in the offspring of affected women. Because it was observed in sibs, NH was classified as a familial hemochromatosis (OMIM 231100). However, clinical evidence now suggests that NH is the consequence of fetal liver injury due to a variety of causes. Most NH is ascribed to gestational alloimmune liver disease (GALD; NH-GALD). GALD can also produce liver disease without extrahepatic siderosis and the absence of siderosis in the newborn liver does not exclude the diagnosis of GALD.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with juvenile hemochromatosis, the evaluations summarized Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.