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Classification and Genetic Features of Neonatal Haemochromatosis: a Study of 27 Avected Pedigrees and Molecular Analysis of Gene

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Classification and Genetic Features of Neonatal Haemochromatosis: a Study of 27 Avected Pedigrees and Molecular Analysis of Gene J Med Genet 2001;38:599–610 599 Classification and genetic features of neonatal J Med Genet: first published as 10.1136/jmg.38.9.599 on 1 September 2001. Downloaded from haemochromatosis: a study of 27 aVected pedigrees and molecular analysis of genes implicated in iron metabolism Alison L Kelly, Peter W Lunt, Fernanda Rodrigues, P J Berry, Diana M Flynn, Patrick J McKiernan, Deirdre A Kelly, Giorgina Mieli-Vergani, Timothy M Cox Abstract Neonatal haemochromatosis (NH, Online Neonatal haemochromatosis (NH) is a Mendelian Inheritance in Man, OMIM severe and newly recognised syndrome of 231100) is a newly recognised and rare uncertain aetiology, characterised by con- syndrome in which congenital cirrhosis or ful- genital cirrhosis or fulminant hepatitis minant hepatitis in early infancy is associated and widespread tissue iron deposition. NH with marked iron deposition in the liver and occurs in the context of maternal disease extrahepatic tissues.1–3 Although the presenta- including viral infection, as a complica- tion of neonatal haemochromatosis with he- tion of metabolic disease in the fetus, and patic failure usually preceded by oligohydram- sporadically or recurrently, without overt nios, placental oedema, and intrauterine Department of cause, in sibs. Although an underlying growth retardation or stillbirth is stereotypical, Medicine, University genetic basis for NH has been suspected, the cause of the condition is ill understood.4–8 of Cambridge, Level 5, no test is available for predictive analysis The liver is generally shrunken and bile stained Box 157, Addenbrooke’s in at risk pregnancies. with extensive fibrosis and nodular regenera- Hospital, Cambridge As a first step towards an understanding tion; there is massive loss of hepatocytes but CB2 2QQ, UK of the putative genetic basis for neonatal surviving cells show giant cell or pseudoglan- A L Kelly haemochromatosis, we have conducted a dular transformation with focal nodular regen- TMCox systematic study of the mode of transmis- eration and varying degrees of cholestasis. Lit- sion of this disorder in a total of 40 infants Clinical Genetics tle inflammation is usually present and most of Service, Institute of born to 27 families. We have moreover the iron deposition is found in the hepatocytes. Child Health, Bristol carried out a molecular analysis of candi- Extrahepatic iron is seen in the acinar cells of Royal Hospital for Sick date genes (â2-microglobulin, HFE, and the pancreas and minor salivary glands as well Children, St Michael’s haem oxygenases 1 and 2) implicated in as the proximal renal tubule, adrenal cortex, Hill, Bristol BS2 8BJ, iron metabolism. No pathogenic muta- 9–11 http://jmg.bmj.com/ UK thyroid, and myocardium. P W Lunt tions in these genes were identified that Although the concentration of iron in the segregate consistently with the disease liver is greatly increased in neonatal haemo- University of Bristol, phenotype in multiplex pedigrees. How- chromatosis, in rare patients who spontane- Department of ever, excluding four pedigrees with clear ously recover and in those patients treated by Paediatric Pathology, evidence of maternal infection associated orthotopic liver transplantation, the excess iron St Michael’s Hospital, with NH, a pedigree showing transmission 12–15 Southwell Street, is apparently redistributed. Since increased Bristol BS2 8EG, UK of maternal antinuclear factor and ribo- liver iron and extrahepatic haemosiderosis may on September 30, 2021 by guest. Protected copyright. P J Berry nucleoprotein antibodies to the aVected rarely result from other causes of liver disease infants, and two families with possible during fetal life,13468 it has been suggested Paediatric Liver matrilineal inheritance of disease in ma- that the iron deposited in neonatal haemochro- Service, King’s College ternal half sibs, a large subgroup of the Hospital, Denmark matosis may not be directly responsible for the aVected pedigrees point to the inheritance 9 Hill, London SE5 9RS, tissue injury. However, in one noteworthy UK of an autosomal recessive trait. This case, severe systemic iron overload with fatal F Rodrigues included 14 pedigrees with aVected and cardiomyopathy and recurrent iron deposition G Mieli-Vergani unaVected infants and a single pedigree in the implanted liver occurred rapidly after where all four aVected infants were the hepatic transplantation.16 It has been further The Liver Unit, The sole oVspring of consanguineous but oth- Birmingham suggested that the extrahepatic parenchymal Children’s Hospital erwise healthy parents. siderosis resembles shunt siderosis in adults NHS Trust, Steelhouse We thus report three distinct patterns of where reduced transferrin concentrations with Lane, Birmingham disease transmission in neonatal haemo- increased iron transferrin saturation leads to B4 6NH, UK chromatosis. In the diVerentiation of a D M Flynn systemic redistribution of iron; in the infant large subgroup showing transmission of with cirrhosis a natural portocaval shunt may P J McKiernan disease in a manner suggesting autosomal D A Kelly develop as a result of the patent ductus recessive inheritance, we also provide the venosus.317 Correspondence to: basis for further genome wide studies to At present the diagnosis of neonatal haemo- Professor T M Cox, define chromosomal determinants of iron chromatosis is dependent on the identification [email protected] storage disease in the newborn. of severe liver disease of intrauterine onset (J Med Genet 2001;38:599–610) Revised version received associated with both hepatic and extrahepatic 15 June 2001 Accepted for publication Keywords: iron storage; haemochromatosis; neonatal; iron deposition that spares cells of the mono- 18 June 2001 liver nuclear phagocyte system.818 The diagnosis www.jmedgenet.com 600 Kelly, Lunt, Rodrigues, et al J Med Genet: first published as 10.1136/jmg.38.9.599 on 1 September 2001. Downloaded from should also exclude primary structural abnor- A (Family 1) malities of the liver, internal exposure to toxins, blood group antigen incompatibility, other I 1 2 metabolic disorders including bile acid synthe- 128 132 126 130 sis defects and tyrosinaemia, infection associ- 128 128 128 130 ated liver disease including cytomegalovirus – – – – (CMV), echovirus, and other agents, as well as – + – – Down’s syndrome.19–23 Neonatal haemochro- matosis has also been associated with birth II defects24 and with distinct syndromes involving the renal tubule, hair growth, and intestinal 34 56 function as well as an acidotic syndrome 126 132 126 128 ND ND recently reported from Finland.25–27 Neonatal 128 128 128 128 ND ND haemochromatosis has been noted in two – – – – – – – + – – – – families where it aVected maternal half sibs, thus raising the possibility of causation by a 28 maternal factor. Evidence for one such factor B (Family 2) has been the description in one family of neo- natal haemochromatosis as part of the neonatal I 12 lupus erythematosus syndrome associated with ND ND ND ND maternal anti-Ro/SS-A and anti-La/SS-B au- 120 126 122 116 29 toantibodies. – – – – About 100 cases of neonatal haemochroma- – + – – tosis have been reported and these show a panethnic distribution with an equal sex II incidence.38 Although the syndrome may on occasion represent the common outcome of 34 several diseases that aVect the fetal liver in ND ND ND ND utero, the disorder also occurs both sporadi- 122 126 ND ND – – – – cally and recurrently in sibs in a manner that is – + – + consistent with transmission as an autosomal recessive trait.2512 However, at present no Figure 1 (A) Pedigree of index family aVected by neonatal haemochromatosis. Haplotypes are displayed in genetic test is available to identify at risk preg- the boxes, representing from top to bottom, alleles of nancies or provide appropriate counselling for chromosome 6p loci in strong linkage with the HFE gene aZicted families. An understanding of the (HLA-F and D6S105) and HFE genotypes (C282Y and H63D) that are associated with adult haemochromatosis. putative genetic basis for neonatal haemochro- ND indicates not done. (B) Pedigree of family with matosis in some families would not only neonatal haemochromatosis showing segregation of improve the outlook for predictive diagnosis chromosome 6p marker alleles as shown in (A). but would provide key information as to its http://jmg.bmj.com/ cause, especially in relation to the molecular oedema and anuria developed. There was little physiology of iron in the fetus. respiratory eVort or spontaneous movement, We have analysed a total of 40 infants hypotension occurred, and death followed at 3 diagnosed with neonatal haemochromatosis days. At necropsy there was moderate jaundice and who were members of 27 families. We have and oedema with an otherwise normal external accordingly conducted a systematic analysis of appearance. The liver had a wrinkled surface the mode of transmission of this condition and with multiple brown-purple nodules up to 1 have categorised possible patterns of inherit- cm in diameter and the spleen was enlarged. on September 30, 2021 by guest. Protected copyright. ance; we have moreover conducted a molecular There was mesenteric haemorrhage but nor- analysis of candidate genes implicated in disor- mal bone marrow appearances. In the lungs ders of iron metabolism. there was focal intra-alveolar haemorrhage and the placenta showed villus oedema. A provi- Patients sional diagnosis of neonatal hepatitis with con- Two index pedigrees form the nucleus of this genital cirrhosis
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