Hemochromatosis, Neonatal

Description

Neonatal hemochromatosis (NH) is characterized by hepatic failure in the newborn period and heavy iron staining in the liver. In addition, there is marked siderosis of extrahepatic tissues, including the heart and pancreas (Driscoll et al., 1988).

Whitington (2007) postulated that some cases of neonatal hemochromatosis result from maternal alloimmunity directed at the fetal liver, and therefore do not represent an inherited mendelian disorder. Other causes may result from metabolic disease or perinatal infection. In particular, he commented that the disorder is not related to the family of inherited liver diseases that fall under the classification of hereditary hemochromatosis (see, e.g., 235200). Whitington (2007) proposed the term 'congenital alloimmune hepatitis.'

In the past, the disorder has loosely been labeled 'neonatal hepatitis' and 'giant cell hepatitis,' which are pathologic findings in the liver representing a common response to a variety of insults, including cholestatic disorders and infection, among others (Fawaz et al., 1975; Knisely et al., 1987; Kelly et al., 2001).

Clinical Features

Knisely et al. (1987) reviewed reported cases of neonatal hemochromatosis, applying rigid criteria as follows: a rapidly progressive clinical course with death in utero or in the early neonatal period; increased tissue iron deposition in multiple sites, particularly in the liver, pancreas, heart, and endocrine glands, with the extrahepatic reticuloendothelial system relatively unaffected; and no evidence for hemolytic disease, syndromes associated with hemosiderosis, or exogenous iron overload from transfusions. Both parents of 1 patient reported by Knisely et al. (1987) had high levels of serum iron and total iron-binding capacity. Knisely et al. (1987) concluded that the available data argued against the suggestion that neonatal hemochromatosis is caused by primary placental hyperabsorption of iron. A bleeding diathesis is often observed. The authors suggested that neonatal hemochromatosis is one of several entities causing the heterogeneous category of disorders often termed giant cell hepatitis, because of pathologic liver findings.

Driscoll et al. (1988) reported 4 cases of NH in 2 families. All patients presented at birth, and the clinical course was characterized by hypoglycemia, hemorrhagic diathesis, and fatal renal and hepatic failure. Postmortem examination showed hepatic fibrosis with a distinctive pattern of iron distribution in the hepatocytes, pancreatic acinar cells, and myocardium. In 1 family, both parents had normal levels of serum iron, iron binding capacity, transferrin, and ferritin levels, but had persistently abnormal liver function tests, which the authors suggested was consistent with mild expressivity of a heterozygous state. In that same family, neither parent nor their 1 infant had the HLA types associated with hereditary hemochromatosis (235200). Driscoll et al. (1988) concluded that NH is an autosomal recessive disorder, and postulated that the combination of expressed maternal heterozygosity and fetal homozygosity produced enhanced iron transport across the placenta, resulting in a marked increase in iron deposition in certain fetal tissues. The authors noted that the clinical course and pathologic findings are distinct from those of Zellweger syndrome (see 214100), hereditary tyrosinemia (276700), and leprechaunism (246200), in which hepatic siderosis is also seen.

Dalhoj et al. (1990) provided a 30-year follow-up of a Danish family reported by Kler and Olesen (1956) in which 6 of 9 sibs had died in utero or neonatally as a result of this disorder. No evidence of hereditary hemochromatosis or other iron storage disease was found in the parents or surviving sibs. Neonatal hemochromatosis also occurs as part of the neonatal lupus erythematosus syndrome, associated with maternal anti-Ro/SS-A (109092) and anti-Ro/SS-B (109090) autoantibodies.

Moerman et al. (1990) reported 4 cases of neonatal hemochromatosis presenting as fulminant hepatic failure. Postmortem examination showed excessive iron deposition in hepatocytes, diffuse hepatic cirrhosis, hepatocellular necrosis, cholestasis, and giant cell transformation. No hemosiderin was detected in the extrahepatic mononuclear-phagocytic cells of the spleen, lymph nodes, or bone marrow. Fetal liver disease had its onset in the late second trimester of pregnancy and was reflected by severe panhypoproteinemia with non-immune hydrops. Hyperbilirubinemia and hemorrhagic diatheses were apparent in the newborns.

Kelly et al. (2001) reported 40 infants with neonatal hemochromatosis from 27 families. The most common presenting features were jaundice, hypoglycemia, and hepatic failure. Laboratory studies showed high serum ferritin and high transferrin saturation (80-90%). Postmortem examination in several patients showed fibrosis with cirrhosis, giant cell transformation, marked iron deposition in hepatocytes, and hepatocelluar necrosis with cholestasis, as well as extensive iron deposition in the myocardium, pancreatic acinar cells, and renal tubules. Thirty of the patients had died at the time of the report.

Shneider et al. (1994) and Siafakas et al. (1997) reported a total of 5 infants with delta-4-3-oxosteroid 5-beta-reductase deficiency (235555) who also had neonatal hemochromatosis.

In a detailed review of the neonatal hemochromatosis, Whitington (2007) noted that liver disease is generally apparent within hours of birth and is one of the most commonly recognized causes of liver failure in the neonate. In rare cases, the liver disease takes a prolonged course and is manifest days to weeks after birth. Late-second and third trimester fetal loss is also commonly observed in the gestational histories of women who have had a baby with NH. Most affected liveborn babies show evidence of fetal insult, such as intrauterine growth restriction and oligohydramnios, and premature birth is common. The presenting clinical features include hypoglycemia, marked coagulopathy, hypoalbuminemia and edema with or without ascites, oliguria, jaundice, and increased serum conjugated and nonconjugated bilirubin. Pathology shows severe liver injury that is out of proportion to that seen in other forms of hemochromatosis. There is cirrhosis and fibrosis, particularly in the lobule and around the central vein, and coarsely granular siderosis. Regenerative nodules may be present. In some instances, almost no hepatocytes remain. The residual and/or regenerating hepatocytes may exhibit either giant cell or pseudoacinar transformation with canalicular bile plugs. Siderosis may affect any of several tissues outside the liver. The prognosis in severe NH is generally very poor, with an average life expectancy of days to a few weeks. There is a very high risk of recurrence in subsequent offspring of an affected woman.

Inheritance

Fienberg (1960) reported 2 pairs of male sibs with perinatal idiopathic hemochromatosis with giant cell hepatitis, and Laurendeau et al. (1961) observed 2 affected sisters, both reports suggesting autosomal recessive inheritance.

Schoenlebe et al. (1993) reported an experience indicating that neonatal hemochromatosis, also known as perinatal hemochromatosis or neonatal iron storage disease, can occur as part of neonatal lupus erythematosus syndrome (see 152700) associated with maternal anti-Ro/SSA (see 109092) and anti-La/SSB (109090) autoantibodies. They reported a 6-week-old girl with neonatal hemochromatosis whose mother had these autoantibodies associated with Sjogren syndrome (see 270150); an older child had congenital heart block.

Verloes et al. (1996) reported 2 families in which neonatal hemochromatosis was observed in half sibs. In the first family, 2 successive girls were born of different fathers. In a second family, an affected brother and sister were followed by an affected half brother born after donor insemination. These observations, as well as a previous abstract describing 2 affected half sisters, revived a debate over the inheritance of neonatal hemochromatosis and suggested causation by a maternal factor. Verloes et al. (1996) tabulated the reported familial cases of typical NH and noted that parental consanguinity was never mentioned.

Kelly et al. (2001) studied 40 infants from 27 families with neonatal hemochromatosis. Four pedigrees had clear evidence of neonatal hemochromatosis associated with maternal infection, including coxsackievirus, E. coli bacteremia and candidiasis, Staphylococcus aureus, and Herpes simplex virus and candidiasis. One pedigree showed transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and 2 families showed possible matrilineal inheritance of disease in maternal half sibs. Fourteen pedigrees included affected and unaffected infants, and a single pedigree had all 4 infants affected by the condition born to consanguineous but otherwise healthy parents. The authors suggested that these 14 pedigrees support autosomal recessive inheritance of this condition in at least some families.

Pathogenesis

Whitington (2007) and Whitington and Kelly (2008) presented evidence that neonatal hemochromatosis is a gestational disease in which fetal liver injury leads to the phenotype in the neonate. The rate of recurrence of the disorder in humna sibs after the index case is 60 to 80%, suggesting maternal alloimmunity against the fetal liver. Preliminary studies found that pregnant mice injected with human IgG from women whose babies had NH had pups with extensive hepatic injury and liver necrosis.

Clinical Management

Based on the hypothesis that neonatal hemochromatosis results from maternal alloimmunity, Whitington and Kelly (2008) treated 48 women with a history of having an affected fetus with IV Ig. The gestational histories of these women demonstrated the high risk of occurrence of neonatal hemochromatosis: 92% of at-risk pregnancies had resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant. In contrast, with IV Ig gestational therapy, 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. Two of the 3 failures were not related to NH; the remaining case was lost to follow-up. Whitington and Kelly (2008) concluded that most cases of neonatal hemochromatosis result from a gestational alloimmune disease and that the occurrence of severe neonatal hemochromatosis in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous Ig during gestation.

Molecular Genetics

Hardy et al. (1990) sought evidence for major rearrangements or deletions at the HLA class I region and at 3 loci directly involved in iron metabolism (H- and L-apoferritin and the transferrin receptor) in neonatal hemochromatosis. In 10 affected probands and 26 first-degree relatives in a total of 13 kindreds, they found no evidence for major rearrangements or deletions in genes studied, and found no evidence for linkage of neonatal hemochromatosis to HLA serotypes. Hardy et al. (1990) concluded that whereas hereditary hemochromatosis and neonatal hemochromatosis are similar in their patterns of iron loading, they are not genetically related.

In several families with neonatal hemochromatosis, Kelly et al. (2001) carried out molecular analysis of the beta-2 microglobulin gene (109700), the HFE gene (613609), and the heme oxygenase-1 and -2 genes (141250; 141251) and found no evidence of pathogenic mutations in any of these genes segregating with the disease phenotype.