American J o u r n a l of Medical Genetics 37:342-345 (1990)
Iron Storage Disease in Parents and Sibs of Infants With Neonatal Hemochromatosis: 30-Year Follow-Up Jorgen Dalhoj, Henrik Kiaer, Preben Wiggers, Robert W. Grady, Robert L. Jones, and A. S. Knisely Arvepatologisk Institut, Odense Universitet, Odense (J.D., P. W.); Patologisk Institut, Svendborg Sygehus, Svendborg (H.K.), Denmark; Department of Pediatrics (Division of HematologylOncology), The New York Hospital-Cornell Medical Center, New York (R.W.G.); Rockefeller University Hospital, Rockefeller University, New York (R.L.J.); Departments of Hematology and Pathology, University of Utah School of Medicine, Salt Lake City, Utah (A.S.K.)
Neonatal hemochromatosis (NH), an uncommon and generally fatal disorder of infancy, is defined by hepatic disease of antenatal onset, generally manifest at birth, and by stainable iron in a tissue distribution like that seen in heritable adult-onset hemochromatosis (HH). It is not known if parents and sibs of infants with NH are at risk of iron storage disease in later life. We provide 30-year follow-up for iron overload of a family in which 6 of 9 children died in utero or early in the neonatal period. Four of the 6 came to autopsy, where severe liver disease was found; in 3 of the 4, autopsy material could be reviewed. These 3 children had NH. Studies 30 years later did not identify HH or other iron storage disease in the parents or surviving sibs. These findings suggest that first-degree relatives of persons with NH are not necessarily at increased risk of iron storage disease in later life. KEY WORDS: cytoferrin, heritable adult-onset hemochromatosis, HLA types, iron, iron storage disease, neonatal hemochromatosis, recurrence risk INTRODUCTION Neonatal hemochromatosis (NH) is a clinicopathologic entity characterized by recurrence in sibships, severe idiopathic liver disease manifest within hours or days of birth, and an abundance of stainable iron in many tissues, with sparing of reticuloendothelial elements [Knisely et al., 1987; Silver et al., 1987; Witzleben and Uri, 19891.This pattern of iron deposition also is present in heritable adult-onset hemochromatosis Received for publication October 9, 1989; revision received Febn d r y 23, 1990.
Address reprint requests to Dr. A S . Knisely, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132.
0 1990 Wiley-Liss, Inc.
(HH) [Sheldon, 19351, a disorder linked to the human leukocyte antigen (HLA)locus on chromosome 6 [Simon et al., 19871. HLA alloantigens often associated with HH have been found in infants with NH and their parents [Glista et al., 1986; Drut et al., 1987; Silver et al., 1987; Colletti and Clemmons, 1988; Knisely et al., 1989b1,and HH has been reported in the father of 2 such infants [Glista et al., 19861. While these associations may be simply coincidental [Hardy et al., 19901, HH often is clinically apparent only in late middle age. It is possible that because iron storage disease may go unrecognized in persons in their reproductive years, longterm follow-up of parents or sibs of infants with NH is necessary to assess the incidence of HH in this group. We report on a family in which such long-term follow-up was possible.
METHODS A search for possible cases of NH in the older literature identified a report of a family in which 6 of 9 sibs had died in utero or neonatally [Kiaer and Olesen, 19561. Four of the 6 came to autopsy, and advanced liver disease was identified in each. Paraffin-embedded, formalin-fixed material from 3 of the 4 (individuals IV-29, -30, and -31) (Fig. 1) was retrieved from hospital archives and parallel sections were stained with hematoxylin and eosin and for iron. Hepatic findings, with extensive diffuse fibrosis, focal nodular regeneration, widespread giant cell and pseudoacinar transformation of remaining hepatocytes, and cholestasis, were as described in the original report. Histopathologic evidence for infective or metabolic disease of definable etiology was not present. Stainable iron was not seen in spleen or lymph nodes but was abundant in hepatocytes and the epithelia of pancreatic exocrine acini (Fig. 2). These findings met clinicopathologic criteria for NH [Knisely et al., 1987;Silver et al., 1987;Witzleben andUri, 19891. The parents and sibs of the affected children were still alive and available for study. None had clinical signs or symptoms of liver disease or of iron storage disease; studies at the time the affected children were born had failed to identify maternal liver disease [Kiaer and Oleson, 19561. The father had atherosclerotic vascular disease manifested as angina pectoris and the mother
Follow-Up in Neonatal Hemochromatosis
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severe liver Fig. 1. Extended pedigree of family studied. 0 ,neonatal hemochromatosisat autopsy;a, disease at autopsy; not reviewed; Ki @, death aged 2 days; no autopsy; 0, stillborn, no autopsy.
best interpreted as coincidental. However, the absence of conclusive evidence for HH is still compatible with heritable iron storage disease. Heritable forms of idiopathic iron storage disease other than classic HH have been identified [Eason et al., 19881, and NH may be such a disorder. It is generally accepted that elevated values for transferrin saturation and for iron and ferritin concentrations in serum reflect elevated body iron stores [Edwards et al., 19881. By these criteria, no evidence of iron storage disease was present after 30 years in the parents and sibs of infants who died of NH. Because the concentration of cytoferrin in serum from an unrelated infant with NH had been found to be markedly elevated [Knisely et al., 1989a1, cytoferrin also was measured in sera from the parents and sibs. Cytoferrin values were normal, suggesting that determinations of cytoferrin concentrations may not identify first-degree relatives of persons with NH. Our findings are consistent with the hypothesis that DISCUSSION NH is an autosomal-recessive disorder and that heteroParental partial haplotypes were (Aw19, B40)/(A1, zygotes are not at increased risk of iron storage disease. B7) in the mother and (A3, B7)/(A28,B18) in the father. They are also consistent with the hypothesis that NH is While the (A3, B7) haplotype is associated with HH a nonspecific end result. NH is a phenotypically defined [Simon et al., 19871,neither the father nor the one child disorder, and it is possible that various insults during with that haplotype (Table I) showed evidence of high fetal life, including infectious or toxic agents as well as body iron stores. HLA typing of several kindreds in metabolic abnormalities, may result in the NH phewhich NH has occurred has indicated that HLA haplo- notype [Knisely et al., 1987; Witzleben and Uri, 1989; type associations characteristic for HH are not neces- Hoogstraten et al., 19901. Genetic counsellors should be sarily present in NH [Hardy et al., 19901. It may be that aware that parents and sibs of persons with NH are not the presence of the (A3, B7) haplotype in this kindred is necessarily at increased risk of iron storage disease.
had biopsy-confirmed sarcoidosis, identified several years before this study; the children were well. All 5 agreed to permit investigation for iron storage disease. Peripheral venous blood was obtained from each. Using standard techniques, hematocrits, hemoglobin concentrations, and erythrocyte indices were determined, HLA serotyping was performed on lymphocytes, and transferrin saturation and serum concentrations of iron, ferritin, and cytoferrin, a low-molecular-weightiron-binding compound [Jones et al., 19871 were measured. The results are given in Table I. Relatives were interviewed and a pedigree was constructed. Death in infancy or in utero was identified in only one other remotely related sibship (individuals 11-9 through 11-14](Fig. 1).No information could be obtained on the attributed causes of death for these sibs. Histories ofhereditary liver disease or known iron storage disease could not be elicited from individuals interviewed.
344
D a l h ~ jet al.
Fig. 2. Pancreas, individual IV-29. Abundant stainable iron is present within acinar epithelial cells. Acid ferrocyanidehuclear fast red (Gomori iron stain), X 240; bar = 60 pm,
TABLE I. Clinical-laboratory Data in Parents and Sibs Hemoglobin (mmollL), hematocrit, erythrocyte volume (L) Standard values 8-11 mmollL (M), 7-10 mmol1L (W); 81-109 fL Mother (111-5) 8.5142190 Father (111-6) 9.7149187 8.7142193 Sister (IV-21) 9.3145191 Sister (IV-23) Sister (IV-25) 8.4140191
Partial HLA haplotypes (serotypes)
Serum iron (pmoll L) 9-35
A l , B7; Aw19, B40 A3, B7: A28. B18 Aw'l9, B40; A28, B18 Cwl, w3 A l , B7; A28, B18 Cwl A3, B7; Aw19, B40 Cw3
16 20.5 18 19 12
-
Serum transferrin Serum (FmollL) and ferritin (FglL) saturation (%) 21-36; < 62%b 15-350 30, 53% 36. 57% 33.5, 54% 38, 50% 35.5, 34%
100 187 20 102 18
Serum cytoferrin (pg/L)a 17.513.7 18.5 10.5 ~. ~
18.0 17.5 18.5
"Expressed in terms of the quantity of deferoxamine required to permit similar growth [Jones et al., 19871. bNormal for fasted populations [Edwards et al., 19881; probands were not fasted, and true transferrin saturations were presumably lower.
ACKNOWLEDGEMENTS This work was supported in part by grants from the Cooley's Anemia Foundation, the Hackett Foundation, and the Wolhardt-Warrer Foundation, by grant R01AM31521 frsm the US.Public Health Service, by grant RR-001202 from the General Clinical Research Center, and by grant 5T32 DK07115 from the National Institutes of Health. R.L.J. is the recipient of a PHS Research Career Development Award. This paper was presented in part a t the interim meeting of the Society for Pedi-
atric Pathology, Washington, D.C., September 17-19, 1987 (Pediatr Pathol7:489,1987). We thank Dr. Don B. Singer for his continued interest, support, and assistance.
REFERENCES Colletti RB, Clemmons JJW (1988): Familial neonatal hemochromatosis with survival. J Pediatr Gastroenterol Nutr 7:39-45. Drut RM, Itarte H, Drut R (1987): Hematocromatosis neonatal idiopatica. Arch Arg Pediatr 85:31-35.
Follow-Up in Neonatal Hemochromatosis Eason R, Adams PC, Aston CE, Searle J (1988): Non-HLA linked hemochromatosis in a Melanesian family: A different iron storage disease with autosomal dominant heritability. Am J Hum Genet 43 (suppl):A47 (abst). Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner J P (1988): Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355-1362. Glista BA, Bautista A, Prudencio M, Desposito F (1986): Neonatal iron storage disease. Pediatr Res 20:410A (abst). Hardy L, Hansen JL, Kushner JP, Knisely AS (1990): Neonatal hemochromatosis: Genetic analysis of transferrin-receptor, H-apoferritin, and L-apoferritin loci and of the HLA class I region. Am J Pathol, in press. Hoogstraten J, de Sa DJ, Knisely AS (1990): Fetal liver disease may precede extrahepatic siderosis in neonatal hemochromatosis. Gastroenterology, 98:1699-1702. Jones RL, Grady RW, Sorette MP, Cerami A (1987): Host-associated iron transfer factor in normal humans and patients with transfusion siderosis. J Lab Clin Med 110:690-705. Kiaer W, Olesen M (1956): Hepatitis foetalis med perinatal exitus letalis hos 4 s0skende. Ugeskr Laeg 118:868-872. Knisely AS, Magid MS, Dische MR, Cutz E (1987): Neonatal hemochromatosis. In Gilbert EF, Opitz JM (eds): “Genetic Aspects of
345
Developmental Pathology.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes, BD: OAS XXIII (1):75-102. Knisely AS, Grady RW, Kramer EE, Jones RL (1989a): Cytoferrin, maternofetal iron transport, and neonatal hemochromatosis. Am J Clin Pathol 92:755-759. Knisely AS, Harford JB, Klausner RD, Taylor SR (198913): Neonatal hemochromatosis: The regulation of transferrin-receptor and ferritin synthesis by iron in cultured fibroblastic-line cells. Am J Pathol 134:439-445. Sheldon J (1935): “Haemochromatosis.” London: Oxford University Press. Silver MM, Beverley DW, Valberg LS, Cutz E, Phillips MJ, Shaheed WA (1987): Perinatal hemochromatosis: Clinical, morphologic, and quantitative iron studies. Am J Path01 128538-554. Simon M, Le Mignon L, Fauchet R, Yaouang J , David V, Gilles E, Bourel M (1987): A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1)mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 41:89-105. Witzleben CL, Uri A (1989):Perinatal hemochromatosis: Entity or end result? Hum Pathol 20:335-340.
Iron Storage Disease in Parents and Sibs of Infants With Neonatal Hemochromatosis: 30-Year Follow-Up Jorgen Dalhoj, Henrik Kiaer, Preben Wiggers, Robert W. Grady, Robert L. Jones, and A. S. Knisely Arvepatologisk Institut, Odense Universitet, Odense (J.D., P. W.); Patologisk Institut, Svendborg Sygehus, Svendborg (H.K.), Denmark; Department of Pediatrics (Division of HematologylOncology), The New York Hospital-Cornell Medical Center, New York (R.W.G.); Rockefeller University Hospital, Rockefeller University, New York (R.L.J.); Departments of Hematology and Pathology, University of Utah School of Medicine, Salt Lake City, Utah (A.S.K.)
Neonatal hemochromatosis (NH), an uncommon and generally fatal disorder of infancy, is defined by hepatic disease of antenatal onset, generally manifest at birth, and by stainable iron in a tissue distribution like that seen in heritable adult-onset hemochromatosis (HH). It is not known if parents and sibs of infants with NH are at risk of iron storage disease in later life. We provide 30-year follow-up for iron overload of a family in which 6 of 9 children died in utero or early in the neonatal period. Four of the 6 came to autopsy, where severe liver disease was found; in 3 of the 4, autopsy material could be reviewed. These 3 children had NH. Studies 30 years later did not identify HH or other iron storage disease in the parents or surviving sibs. These findings suggest that first-degree relatives of persons with NH are not necessarily at increased risk of iron storage disease in later life. KEY WORDS: cytoferrin, heritable adult-onset hemochromatosis, HLA types, iron, iron storage disease, neonatal hemochromatosis, recurrence risk INTRODUCTION Neonatal hemochromatosis (NH) is a clinicopathologic entity characterized by recurrence in sibships, severe idiopathic liver disease manifest within hours or days of birth, and an abundance of stainable iron in many tissues, with sparing of reticuloendothelial elements [Knisely et al., 1987; Silver et al., 1987; Witzleben and Uri, 19891.This pattern of iron deposition also is present in heritable adult-onset hemochromatosis Received for publication October 9, 1989; revision received Febn d r y 23, 1990.
Address reprint requests to Dr. A S . Knisely, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132.
0 1990 Wiley-Liss, Inc.
(HH) [Sheldon, 19351, a disorder linked to the human leukocyte antigen (HLA)locus on chromosome 6 [Simon et al., 19871. HLA alloantigens often associated with HH have been found in infants with NH and their parents [Glista et al., 1986; Drut et al., 1987; Silver et al., 1987; Colletti and Clemmons, 1988; Knisely et al., 1989b1,and HH has been reported in the father of 2 such infants [Glista et al., 19861. While these associations may be simply coincidental [Hardy et al., 19901, HH often is clinically apparent only in late middle age. It is possible that because iron storage disease may go unrecognized in persons in their reproductive years, longterm follow-up of parents or sibs of infants with NH is necessary to assess the incidence of HH in this group. We report on a family in which such long-term follow-up was possible.
METHODS A search for possible cases of NH in the older literature identified a report of a family in which 6 of 9 sibs had died in utero or neonatally [Kiaer and Olesen, 19561. Four of the 6 came to autopsy, and advanced liver disease was identified in each. Paraffin-embedded, formalin-fixed material from 3 of the 4 (individuals IV-29, -30, and -31) (Fig. 1) was retrieved from hospital archives and parallel sections were stained with hematoxylin and eosin and for iron. Hepatic findings, with extensive diffuse fibrosis, focal nodular regeneration, widespread giant cell and pseudoacinar transformation of remaining hepatocytes, and cholestasis, were as described in the original report. Histopathologic evidence for infective or metabolic disease of definable etiology was not present. Stainable iron was not seen in spleen or lymph nodes but was abundant in hepatocytes and the epithelia of pancreatic exocrine acini (Fig. 2). These findings met clinicopathologic criteria for NH [Knisely et al., 1987;Silver et al., 1987;Witzleben andUri, 19891. The parents and sibs of the affected children were still alive and available for study. None had clinical signs or symptoms of liver disease or of iron storage disease; studies at the time the affected children were born had failed to identify maternal liver disease [Kiaer and Oleson, 19561. The father had atherosclerotic vascular disease manifested as angina pectoris and the mother
Follow-Up in Neonatal Hemochromatosis
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severe liver Fig. 1. Extended pedigree of family studied. 0 ,neonatal hemochromatosisat autopsy;a, disease at autopsy; not reviewed; Ki @, death aged 2 days; no autopsy; 0, stillborn, no autopsy.
best interpreted as coincidental. However, the absence of conclusive evidence for HH is still compatible with heritable iron storage disease. Heritable forms of idiopathic iron storage disease other than classic HH have been identified [Eason et al., 19881, and NH may be such a disorder. It is generally accepted that elevated values for transferrin saturation and for iron and ferritin concentrations in serum reflect elevated body iron stores [Edwards et al., 19881. By these criteria, no evidence of iron storage disease was present after 30 years in the parents and sibs of infants who died of NH. Because the concentration of cytoferrin in serum from an unrelated infant with NH had been found to be markedly elevated [Knisely et al., 1989a1, cytoferrin also was measured in sera from the parents and sibs. Cytoferrin values were normal, suggesting that determinations of cytoferrin concentrations may not identify first-degree relatives of persons with NH. Our findings are consistent with the hypothesis that DISCUSSION NH is an autosomal-recessive disorder and that heteroParental partial haplotypes were (Aw19, B40)/(A1, zygotes are not at increased risk of iron storage disease. B7) in the mother and (A3, B7)/(A28,B18) in the father. They are also consistent with the hypothesis that NH is While the (A3, B7) haplotype is associated with HH a nonspecific end result. NH is a phenotypically defined [Simon et al., 19871,neither the father nor the one child disorder, and it is possible that various insults during with that haplotype (Table I) showed evidence of high fetal life, including infectious or toxic agents as well as body iron stores. HLA typing of several kindreds in metabolic abnormalities, may result in the NH phewhich NH has occurred has indicated that HLA haplo- notype [Knisely et al., 1987; Witzleben and Uri, 1989; type associations characteristic for HH are not neces- Hoogstraten et al., 19901. Genetic counsellors should be sarily present in NH [Hardy et al., 19901. It may be that aware that parents and sibs of persons with NH are not the presence of the (A3, B7) haplotype in this kindred is necessarily at increased risk of iron storage disease.
had biopsy-confirmed sarcoidosis, identified several years before this study; the children were well. All 5 agreed to permit investigation for iron storage disease. Peripheral venous blood was obtained from each. Using standard techniques, hematocrits, hemoglobin concentrations, and erythrocyte indices were determined, HLA serotyping was performed on lymphocytes, and transferrin saturation and serum concentrations of iron, ferritin, and cytoferrin, a low-molecular-weightiron-binding compound [Jones et al., 19871 were measured. The results are given in Table I. Relatives were interviewed and a pedigree was constructed. Death in infancy or in utero was identified in only one other remotely related sibship (individuals 11-9 through 11-14](Fig. 1).No information could be obtained on the attributed causes of death for these sibs. Histories ofhereditary liver disease or known iron storage disease could not be elicited from individuals interviewed.
344
D a l h ~ jet al.
Fig. 2. Pancreas, individual IV-29. Abundant stainable iron is present within acinar epithelial cells. Acid ferrocyanidehuclear fast red (Gomori iron stain), X 240; bar = 60 pm,
TABLE I. Clinical-laboratory Data in Parents and Sibs Hemoglobin (mmollL), hematocrit, erythrocyte volume (L) Standard values 8-11 mmollL (M), 7-10 mmol1L (W); 81-109 fL Mother (111-5) 8.5142190 Father (111-6) 9.7149187 8.7142193 Sister (IV-21) 9.3145191 Sister (IV-23) Sister (IV-25) 8.4140191
Partial HLA haplotypes (serotypes)
Serum iron (pmoll L) 9-35
A l , B7; Aw19, B40 A3, B7: A28. B18 Aw'l9, B40; A28, B18 Cwl, w3 A l , B7; A28, B18 Cwl A3, B7; Aw19, B40 Cw3
16 20.5 18 19 12
-
Serum transferrin Serum (FmollL) and ferritin (FglL) saturation (%) 21-36; < 62%b 15-350 30, 53% 36. 57% 33.5, 54% 38, 50% 35.5, 34%
100 187 20 102 18
Serum cytoferrin (pg/L)a 17.513.7 18.5 10.5 ~. ~
18.0 17.5 18.5
"Expressed in terms of the quantity of deferoxamine required to permit similar growth [Jones et al., 19871. bNormal for fasted populations [Edwards et al., 19881; probands were not fasted, and true transferrin saturations were presumably lower.
ACKNOWLEDGEMENTS This work was supported in part by grants from the Cooley's Anemia Foundation, the Hackett Foundation, and the Wolhardt-Warrer Foundation, by grant R01AM31521 frsm the US.Public Health Service, by grant RR-001202 from the General Clinical Research Center, and by grant 5T32 DK07115 from the National Institutes of Health. R.L.J. is the recipient of a PHS Research Career Development Award. This paper was presented in part a t the interim meeting of the Society for Pedi-
atric Pathology, Washington, D.C., September 17-19, 1987 (Pediatr Pathol7:489,1987). We thank Dr. Don B. Singer for his continued interest, support, and assistance.
REFERENCES Colletti RB, Clemmons JJW (1988): Familial neonatal hemochromatosis with survival. J Pediatr Gastroenterol Nutr 7:39-45. Drut RM, Itarte H, Drut R (1987): Hematocromatosis neonatal idiopatica. Arch Arg Pediatr 85:31-35.
Follow-Up in Neonatal Hemochromatosis Eason R, Adams PC, Aston CE, Searle J (1988): Non-HLA linked hemochromatosis in a Melanesian family: A different iron storage disease with autosomal dominant heritability. Am J Hum Genet 43 (suppl):A47 (abst). Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner J P (1988): Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355-1362. Glista BA, Bautista A, Prudencio M, Desposito F (1986): Neonatal iron storage disease. Pediatr Res 20:410A (abst). Hardy L, Hansen JL, Kushner JP, Knisely AS (1990): Neonatal hemochromatosis: Genetic analysis of transferrin-receptor, H-apoferritin, and L-apoferritin loci and of the HLA class I region. Am J Pathol, in press. Hoogstraten J, de Sa DJ, Knisely AS (1990): Fetal liver disease may precede extrahepatic siderosis in neonatal hemochromatosis. Gastroenterology, 98:1699-1702. Jones RL, Grady RW, Sorette MP, Cerami A (1987): Host-associated iron transfer factor in normal humans and patients with transfusion siderosis. J Lab Clin Med 110:690-705. Kiaer W, Olesen M (1956): Hepatitis foetalis med perinatal exitus letalis hos 4 s0skende. Ugeskr Laeg 118:868-872. Knisely AS, Magid MS, Dische MR, Cutz E (1987): Neonatal hemochromatosis. In Gilbert EF, Opitz JM (eds): “Genetic Aspects of
345
Developmental Pathology.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes, BD: OAS XXIII (1):75-102. Knisely AS, Grady RW, Kramer EE, Jones RL (1989a): Cytoferrin, maternofetal iron transport, and neonatal hemochromatosis. Am J Clin Pathol 92:755-759. Knisely AS, Harford JB, Klausner RD, Taylor SR (198913): Neonatal hemochromatosis: The regulation of transferrin-receptor and ferritin synthesis by iron in cultured fibroblastic-line cells. Am J Pathol 134:439-445. Sheldon J (1935): “Haemochromatosis.” London: Oxford University Press. Silver MM, Beverley DW, Valberg LS, Cutz E, Phillips MJ, Shaheed WA (1987): Perinatal hemochromatosis: Clinical, morphologic, and quantitative iron studies. Am J Path01 128538-554. Simon M, Le Mignon L, Fauchet R, Yaouang J , David V, Gilles E, Bourel M (1987): A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1)mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 41:89-105. Witzleben CL, Uri A (1989):Perinatal hemochromatosis: Entity or end result? Hum Pathol 20:335-340.
