Other entities represented in this entry:
SNOMEDCT: 50855007; ORPHA: 79230; DO: 0111027;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.1 | Hemochromatosis, type 2A | 602390 | Autosomal recessive | 3 | HJV | 608374 |
A number sign (#) is used with this entry because juvenile hemochromatosis type 2A (HFE2A) is caused by homozygous or compound heterozygous mutation in the gene encoding hemojuvelin (HJV; 608374) on chromosome 1q21.
For a general phenotypic description and a discussion of genetic heterogeneity of hereditary hemochromatosis, see 235200.
Juvenile, or type 2, hemochromatosis is an autosomal recessive inborn error of iron metabolism that leads to severe iron loading and organ failure before 30 years of age. The common complications of iron overload, including liver cirrhosis, cardiac disease, endocrine failure, diabetes, arthropathy, and skin pigmentation, are similar to those of adult-onset hereditary hemochromatosis, but hypogonadism and cardiomyopathy are the most common symptoms at presentation. Heart failure and/or major arrhythmias are usually the cause of death in the absence of treatment. Early detection of the disorder is important because iron depletion by phlebotomy can prevent organ damage and all disease manifestations (summary by Roetto et al., 1999).
Genetic Heterogeneity of Hemochromatosis Type 2
Hemochromatosis type 2B (HFE2B; 613313) is caused by mutation in the hepcidin gene (HAMP; 606464) on chromosome 19q13.
Cazzola et al. (1983) emphasized the special characteristics of juvenile hemochromatosis: onset with abdominal pain in the first decade, hypogonadotropic hypogonadism in the second decade, and cardiac arrhythmias and intractable heart failure in the third decade. Males and females are affected about equally.
Cazzola et al. (1983) described the disorder in an Italian brother and sister and in German identical twins. They pointed to the cases of Perkins et al. (1965), Felts et al. (1967), Charlton et al. (1967), and Lamon et al. (1979) as examples of the same disorder.
Although the organ damage in JH is more severe, parenchymal iron distribution is similar to that in HFE, as inferred by liver biopsies or autopsy findings (Molitch and Kirkham, 1983; Haddy et al., 1988). Reports of functional studies on iron metabolism in JH are limited. Camaschella et al. (1997) cited 1 published case in which iron absorption was 100%, despite the severe iron load, a value never reached in HFE.
Camaschella et al. (1997) described 7 Italian patients belonging to 5 unrelated families with features typical of JH. In 4 of the 5 families, the parents were consanguineous. Analysis of HFE gene (613609) mutations in all cases and nucleotide sequence of the gene in one case excluded the HFE gene as responsible for JH. Furthermore, segregation analysis of 6p markers closely associated with HFE showed that JH is unlinked to 6p and thus genetically distinct from HFE.
Cazzola et al. (1998) reported molecular studies in 2 Italian families with juvenile hemochromatosis, 1 of which was reported by Cazzola et al. (1983). Both families had an affected brother and sister. Of the 4 affected individuals, 3 presented with hypogonadotropic hypogonadism at 14 to 21 years of age. The affected male of 1 family presented with cardiac failure at 20 years of age and died at 21 years of age with congestive cardiomyopathy. All the family members examined were negative for the C282Y (613609.0001) and H63D (613609.0002) mutations of the HFE gene. Three of the patients underwent regular phlebotomies. Based on the amount of iron mobilized by bleedings, Cazzola et al. (1998) estimated that these patients had body iron stores ranging from 220 to 329 mg/kg of body weight at the time of diagnosis at 17 to 21 years of age. Based on phlebotomy requirements for maintenance of normal iron balance, the rate of estimated iron accumulation ranged from 3.2 to 3.9 mg/d. This was clearly higher than the rate of 0.8 to 1.6 mg/d found in 5 adult males homozygous for the C282Y mutation. This remarkable difference in iron overprocurement suggested completely different pathogenetic mechanisms.
Kelly et al. (1998) reported 4 patients (2 of each sex) from 3 pedigrees affected by juvenile hemochromatosis with a mean onset at 22 years. All had endocrine deficiency with postpubertal gonadal failure secondary to pituitary disease; 2 suffered near-fatal cardiomyopathy with heart failure. A 24-year-old man listed for heart transplantation because of cardiomyopathy responded to intravenous iron chelation with desferrioxamine combined with phlebotomy and did not require transplantation. A 27-year-old woman required orthotopic cardiac transplantation before the diagnosis was established. These 2 patients with cardiomyopathy from unrelated families were heterozygous for the C282Y mutation of the HFE gene and did not have the H63D mutation.
De Gobbi et al. (2002) analyzed the phenotype of 29 patients with JH, from 20 families of different ethnic origin, with linkage to chromosome 1q. They also compared the clinical expression in 26 of these patients with that of 93 males homozygous for the C282Y mutation (613609.0001) and with that of 11 patients with hemochromatosis type 3 (604250), which is caused by mutation in the transferrin receptor-2 gene (TFR2; 604720). Patients with JH were statistically younger at presentation and had a more severe iron burden than C282Y homozygotes and hemochromatosis type 3 patients. They were more frequently affected by cardiopathy, hypogonadism, and reduced glucose tolerance. In contrast, cirrhosis was not statistically different among the 3 groups. The data suggested that the rapid iron accumulation in JH causes preferential tissue damage. The results clarified the natural history of the disease and were compatible with the hypothesis that the implicated gene at the HFE2 locus on 1q has greater influence on iron absorption than other hemochromatosis-associated genes.
Murugan et al. (2008) reported a 23-year-old African American man of West Indies descent who was first diagnosed with iron overload at age 4 years. At that time, he had iron deposition in the liver and began treatment with phlebotomy. He developed normally as a teen but developed splenomegaly with cirrhosis and portal hypertension by age 23. However, he did not have cardiomyopathy or hypogonadotrophic hypogonadism. His paternal grandparents came from Tobago and Grenada, and his maternal grandparents were from Trinidad and Grenada. There was no family history of consanguinity, iron overload, or Caucasian or white admixture. His parents and sister had normal iron phenotypes.
Roetto et al. (1999) performed a genomewide search to map the HFE2 locus in 9 families, 6 consanguineous and 3 with multiple affected persons. They located the gene on 1q, with a maximum lod score of 5.75 at a recombination fraction of 0.0 with marker D1S498, and a lod score of 5.16 at a recombination fraction of 0.0 with marker D1S2344. Homozygosity mapping in consanguineous families defined the limits of the candidate region in an interval of approximately 4 cM between D1S442 and D1S2347 on 1q21. The HFE2 locus did not correspond to the chromosomal localization of any known gene involved in iron metabolism.
Rivard et al. (2003) performed linkage analysis of 17 French Canadian patients with JH from the Saguenay-Lac-Saint-Jean region and confirmed linkage to the HFE2A locus on chromosome 1q. They obtained a maximum lod of 4.07 at theta = 0.0 with markers D1S2344 and D1S1156. Rivard et al. (2003) identified a common ancestral haplotype, suggesting the presence of a founder mutation.
Papanikolaou et al. (2004) reported the positional cloning of the 1q locus associated with juvenile hemochromatosis and the identification of a gene (HJV) crucial to iron metabolism, the product of which they called hemojuvelin. Analysis of Greek, Canadian, and French families indicated that 1 mutation in the HJV gene, gly320 to val (G320V; 608374.0001), was present in all 3 populations and accounted for two-thirds of the mutations found.
Lanzara et al. (2004) studied 34 patients with hepcidin-unrelated JH from 29 families and identified 17 different mutations in the HJV gene. Seventeen patients from 12 families of the isolated region of Saguenay-Lac-Saint-Jean in Quebec, who were previously studied by Rivard et al. (2003), were all homozygous for the G320V mutation (608374.0001). In contrast, there was a large variety of HJV mutations among JH patients in 13 Italian families in the study; the only Italian G320V homozygote was likely of Greek ancestry, because he lived in an isolated southern Italian region where a dialect resembling Greek was still spoken.
Gehrke et al. (2005) analyzed the HAMP (606464) and HJV genes in 7 patients with JH from 6 unrelated central European families from Germany, Slovakia, and Croatia. No mutations were found in the HAMP gene. Six of the 7 (86%) patients carried at least 1 copy of the G320V mutation, and 4 were homozygous for the mutation. Gehrke et al. (2005) concluded that the genetic background of JH might be more homogeneous than initially believed. In a Croatian patient who had the most severe phenotype, with liver cirrhosis, severe dilated cardiomyopathy, and hypogonadism, Gehrke et al. (2005) also found a heterozygous C282Y mutation in the HFE gene (613609.0001) and suggested that HFE mutations might influence the phenotypic expression in HJV-related JH.
In a 23-year-old African American man of West Indies descent with hemochromatosis, Murugan et al. (2008) identified a homozygous mutation in the HJV gene (R54X; 608374.0009). Murugan et al. (2008) commented that this disorder is uncommon among African Americans.
In a 21-year-old male patient who initially presented with ventricular fibrillation and developed cardiogenic shock due to global cardiac insufficiency, who was found to have excessive iron storage and hypertrophy on myocardial biopsy, Brakensiek et al. (2009) confirmed the diagnosis of hemochromatosis with serum iron parameters and identified homozygosity for the G320V mutation in the HJV gene. The patient, who died of low cardiac output and multiorgan failure, was also compound heterozygous for the H63D (613609.0002) and S65C (613609.0003) mutations in the HFE gene, but did not have any mutations in the HAMP gene. Brakensiek et al. (2009) suggested that severity of the clinical course in this patient might be related to the complex genotype.
Brakensiek, K., Fegbeutel, C., Malzer, M., Struber, M., Kreipe, H., Stuhrmann, M. Juvenile hemochromatosis due to homozygosity for the G320V mutation in the HJV gene with fatal outcome. (Letter) Clin. Genet. 76: 493-495, 2009. [PubMed: 19796184] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01261.x]
Camaschella, C., Roetto, A., Cicilano, M., Pasquero, P., Bosio, S., Gubetta, L., Di Vito, F., Girelli, D., Totaro, A., Carella, M., Grifa, A., Gasparini, P. Juvenile and adult hemochromatosis are distinct genetic disorders. Europ. J. Hum. Genet. 5: 371-375, 1997. [PubMed: 9450181]
Cazzola, M., Ascari, E., Barosi, G., Claudiani, G., Dacco, M., Kaltwasser, J. P., Panaiotopoulos, N., Schalk, K. P., Werner, E. E. Juvenile idiopathic haemochromatosis: a life-threatening disorder presenting as hypogonadotropic hypogonadism. Hum. Genet. 65: 149-154, 1983. [PubMed: 6418636] [Full Text: https://doi.org/10.1007/BF00286653]
Cazzola, M., Cerani, P., Rovati, A., Iannone, A., Claudiani, G., Bergamaschi, G. Juvenile genetic hemochromatosis is clinically and genetically distinct from the classical HLA-related disorder. (Letter) Blood 92: 2979-2981, 1998. [PubMed: 9763590]
Charlton, R. W., Abrahams, C., Bothwell, T. H. Idiopathic hemochromatosis in young subjects. Arch. Path. 83: 132-140, 1967. [PubMed: 6019566]
De Gobbi, M., Roetto, A., Piperno, A., Mariani, R., Alberti, F., Papanikolaou, G., Politou, M., Lockitch, G., Girelli, D., Fargion, S., cox, T. M., Gasparini, P., Cazzola, M., Camaschella, C. Natural history of juvenile haemochromatosis. Brit. J. Haemat. 117: 973-979, 2002. [PubMed: 12060140] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03509.x]
Felts, J. H., Nelson, J. R., Herndon, C. N., Spurr, C. L. Hemochromatosis in two young sisters: case studies and a family survey. Ann. Intern. Med. 67: 117-123, 1967. [PubMed: 6028643] [Full Text: https://doi.org/10.7326/0003-4819-67-1-117]
Gehrke, S. G., Pietrangelo, A., Kascak, M., Braner, A., Eisold, M., Kulaksiz, H., Herrmann, T., Hebling, U., Bents, K., Gugler, R., Stremmel, W. HJV gene mutations in European patients with juvenile hemochromatosis. Clin. Genet. 67: 425-428, 2005. [PubMed: 15811010] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00413.x]
Haddy, T. B., Castro, O. L., Rana, S. R. Hereditary hemochromatosis in children, adolescents, and young adults. Am. J. Pediat. Hemat. Oncol. 10: 23-34, 1988. [PubMed: 3056060] [Full Text: https://doi.org/10.1097/00043426-198821000-00006]
Kelly, A. L., Rhodes, D. A., Roland, J. M., Schofield, P., Cox, T. M. Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron-storage disease. Quart. J. Med. 91: 607-618, 1998. [PubMed: 10024915] [Full Text: https://doi.org/10.1093/qjmed/91.9.607]
Lamon, J. M., Marynick, S. P., Roseblatt, R., Donnelly, S. Idiopathic hemochromatosis in a young female: a case study and review of the syndrome in young people. Gastroenterology 76: 178-183, 1979. [PubMed: 758139]
Lanzara, C., Roetto, A., Daraio, F., Rivard, S., Ficarella, R., Simard, H., Cox, T. M., Cazzola, M., Piperno, A., Gimenez-Roqueplo, A.-P., Grammatico, P., Volinia, S., Gasparini, P., Camaschella, C. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103: 4317-4321, 2004. [PubMed: 14982873] [Full Text: https://doi.org/10.1182/blood-2004-01-0192]
Molitch, M. E., Kirkham, S. E. Case records of the Massachusetts General Hospital. Case 25-1983: a 30-year-old man with hypogonadism. New Eng. J. Med. 308: 1521-1529, 1983.
Murugan, R. C., Lee, P. L., Kalavar, M. R., Barton, J. C. Early age-of-onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A-T) in an African American male of West Indies descent. Clin. Genet. 74: 88-92, 2008. [PubMed: 18492090] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01017.x]
Papanikolaou, G., Papaioannou, M., Politou, M., Vavatsi, N., Kioumi, A., Tsiatsiou, P., Marinaki, P., Loukopoulos, D., Christakis, J. I. Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of three families of northern Greek origin. Blood Cells Molec. Dis. 29: 168-173, 2002. [PubMed: 12490283] [Full Text: https://doi.org/10.1006/bcmd.2002.0553]
Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L. E., Franchini, P. L., Dube, M.-P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., and 12 others. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nature Genet. 36: 77-82, 2004. [PubMed: 14647275] [Full Text: https://doi.org/10.1038/ng1274]
Perkins, K. W., McInnes, I. W. S., Blackburn, C. R. B., Beal, R. W. Idiopathic hemochromatosis in children: report of a family. Am. J. Med. 39: 118-126, 1965. [PubMed: 14314226] [Full Text: https://doi.org/10.1016/0002-9343(65)90251-2]
Rivard, S. R., Lanzara, C., Grimard, D., Carella, M., Simard, H., Ficarella, R., Simard, R., D'Adamo, A. P., Ferec, C., Camaschella, C., Mura, C., Roetto, A., De Braekeleer, M., Bechner, L., Gasparini, P. Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Europ. J. Hum. Genet. 11: 585-589, 2003. [PubMed: 12891378] [Full Text: https://doi.org/10.1038/sj.ejhg.5201009]
Roetto, A., Totaro, A., Cazzola, M., Cicilano, M., Bosio, S., D'Ascola, G., Carella, M., Zelante, L., Kelly, A. L., Cox, T. M., Gasparini, P., Camaschella, C. Juvenile hemochromatosis locus maps to chromosome 1q. Am. J. Hum. Genet. 64: 1388-1393, 1999. [PubMed: 10205270] [Full Text: https://doi.org/10.1086/302379]