Delphine de Boissieu and A.S. Knisely

Unité de Gastroénterologie Pédiatrique, Hôpital Saint Vincent de Paul, Paris, France

Correspondence:

A.S. Knisely, MD
Liver Institute, King's College Hospital
Denmark Hill, London SE5 9RS, UK
England (UK)

alex.knisely@kcl.ac.uk

Neonatal hemochromatosis (NH; OMIM* 231100) is defined by the coexistence of liver disease of antenatal onset with excess iron at extrahepatic sites in a tissue distribution parallel to that seen in HFE-associated hemochromatosis (OMIM 235200). NH is not a single disorder, but a syndrome. While the etiology of most cases is unclear, NH is not an unusual manifestation of HFE disease. Some instances of NH may be due primarily to defects in tissue iron handling. Most appear to represent fulminant hepatic failure of fetal onset, with altered iron storage as a sequela. In selected cases, mitochondrial DNA analysis or searches for infective agents harbored by parents of NH patients may prove rewarding. Genomic screening for candidate genes has yet to be attempted. Until recently, NH was diagnosed only at autopsy. It now can be identified antenatally, though to date only in the third trimester of pregnancy, and patients have survived with either supportive care or orthotopic liver transplantation.

As discussed elsewhere in this text, hemochromatosis was identified in adults who absorbed dietary iron in excess of body needs and in whom excess tissue iron led to organ dysfunction [1]. (In Europe and the Americas, the great majority of instances of hemochromatosis in adults are due to mutations in HFE, a gene at 6p21.3 with a product of unknown function [2].) With respect to the tissue distribution of iron, the phenotype in hemochromatosis (hemochromatotic siderosis) is different from that seen in iron overload owing to blood transfusions (transfusional siderosis). In transfusional siderosis *OMIM: Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/Omim/). reticuloendothelial elements in spleen, lymph nodes, bone marrow, and along hepatic sinusoids, which take up erythrocytes from the circulation, are the
first site of iron deposition. Siderosis of parenchymal tissues of various organs develops secondarily, and is associated with myocardial and endocrine-system failure [3]. In hemochromatosis periportal hepatocytes, which take up iron absorbed into portal venous plasma from chyme, are the first site of iron deposition. Over time, siderosis extends throughout the hepatic lobule and involves pancreatic parenchyma, myocardium, and some endocrine epithelia. Reticuloendothelial elements remain strikingly iron-free. As in transfusional siderosis, myocardial and endocrine-system failure are seen [1]; cirrhosis, however, seems to be a feature of hemochromatosis rather than of transfusional siderosis uncomplicated by infective hepatitis [4]

It is the phenotype of advanced liver disease together with extrahepatic parenchymal rather than reticuloendothelial siderosis that Hans Cottier was the first to recognize in infants as mimicking late-stage hemochromatosis of adults. In 1957 he described "a disease picture comparable to
hemochromatosis in newborn infants" [5]. Similar observations were published in English for the first time some years later [6, 7], and many reports of NH have since appeared worldwide [8 - 10].

CLINICAL MANIFESTATIONS

NH recurs in sibships. Infants with NH may be stillborn and often are born prematurely or exhibit intrauterine growth retardation. Placental edema and oligohydramnios are frequent complications, although polyhydramnios also has been reported [11, 12]. Liver disease is generally apparent at birth or only hours thereafter: Tests of umbilical cord serum have confirmed that liver disease is present antenatally [13, 14]. It may be that liver disease of fetal onset takes a subacute course and is manifest as NH only days to weeks after birth [10, 14, 15], but such cases are highly exceptional. Liver disease may antedate the development of extrahepatic siderosis in NH [16].

Presenting conditions in NH include hypoglycemia, hypoalbuminemia and edema with or without ascites and oliguria, and a hemorrhagic diathesis with or without elevated levels of fibrin split products, thrombocytopenia, and anemia [8 - 10]. The initial manifestations of NH thus reflect hepatic disease, with presumedly reduced capacity to store glycogen, to release glucose, and to synthesize albumin and clotting factors. Placental edema may be due to decreased oncotic pressure, as may fetal oliguria, manifest as oligohydramnios (but see "Anatomic-pathology findings", below). Hyperbilirubinemia, which develops during the first few days after birth, may be due to impaired hepatic synthesis and excretion of bilirubin as well as (given a hemorrhagic diathesis)