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Selected Summaries: Genetic Counseling in Neonatal Hemochromatosis

Selected Summaries

Braegger, Christian M.D.; Shneider, Benjamin L. M.D.

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Journal of Pediatric Gastroenterology and Nutrition: March 2002 - Volume 34 - Issue 3 - p 328
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Classification and Genetic Features of Neonatal Haemochromatosis: A Study of 27 Affected Pedigrees and Molecular Analysis of Genes Implicated in Iron Metabolism. Kelly D, Lunt P, Rodrigues F, et al. J Med Genet 2001;38:599–610.


The authors report a British multicenter study of the cause of neonatal hemochromatosis (NH). Twenty-seven affected pedigrees were analyzed for clinical features and the pattern of disease inheritance. A few selected pedigrees also were investigated for genetic abnormalities in selected genes involved in iron metabolism (β2-microglobulin, HFE, and hem oxygenases 1 and 2). The authors report three distinct patterns of disease/inheritance: infection associated, maternal based, and apparent autosomal recessive. They identified no association with the iron metabolism genes.


Neonatal hemochromatosis is a devastating illness and presents a difficult task for the clinician who cares for families affected by this disease. Most infants with NH do not survive, and families ask about the cause of their infant's demise and whether this illness will affect future children. Answers to these questions are not available, and the authors' efforts were directed at providing new insights.

In addressing the cause and pattern of the inheritance of NH, precise diagnosis is crucial. The authors state,

“The diagnosis of neonatal haemochromatosis is dependent on the identification of severe liver disease of intrauterine onset associated with both hepatic and extrahepatic iron deposition that spares cells of the mononuclear phagocyte system. Known hepatic disorders including infectious etiologies should be excluded.”

Unfortunately, strict application of these accepted criteria eliminates 14 of the 27 reported affected pedigrees (residual positive families: 1, 2, 4, 13, 14, 16, 19, 20, 21, 22, 24, 25, and 26). Therefore, one must be cautious in accepting the interpretations of this study.

Analysis of the histories of the 13 “well-characterized affected” families suggest a pattern of inheritance other than autosomal recessive. In a total of 39 reported conceptions, 22 infants were affected, 11 were unaffected, and 6 were miscarried. Only 3 of the unaffected children were born after the birth or miscarriage of an affected child. An alternative interpretation of the data would be that NH represents an autosomal dominant trait, an abnormality of a mitochondrial gene, or involves a maternal-based immune-mediated process. Clarifying this is crucial for informed family counseling.

Clearly, further investigations of NH are necessary. Neonatal hemochromatosis may be a final clinicopathologic outcome associated with diseases that cause in utero liver failure, and a variety of disorders probably can cause in utero liver failure. Infectious causes such as the reported Coxsackie B and herpes simplex virus infections are unlikely to recur. These causes should be sought out in all cases, because positive findings have significant implications for genetic counseling. Some cases of NH may result from an autosomal recessive disorder that leads to prenatal hepatic dysfunction. Unfortunately, the data presented suggest that in many cases the prevalence of the disorder in families exceeds that expected from simple recessive inheritance. Therefore, in our center, we counsel families that in the absence of a documented infectious cause, the chance of recurrence is at least 25%. In families in which two consecutive children are affected or with a history of an antecedent miscarriage, we caution that there is a significantly higher if not certain chance of recurrence. Careful obstetrical follow-up is essential in these cases, as is the need for delivery in a center experienced in the care of neonates with liver failure. Maternal therapy in this disorder may hold great promise (P. F. Whitington Materno-Fetal Issues in Liver Disease. October 27, 2000. Dallas, Texas).

© 2002 Lippincott Williams & Wilkins, Inc.