neonatal hemochromatosis

Definition: Neonatal hemochromatosis is an uncommon disorder, clinicopathologically defined by severe and generally fatal liver disease of intrauterine onset associated with extrahepatic siderosis that spares reticuloendothelial elements (hemochromatotic siderosis).

Beginning as a fetal liver disease, it typically presents as liver failure
in newborn infants that are often born prematurely and with intrauterine growth restriction caused by prenatal insult.

Many cases of NH are due to maternal alloimmunity directed at the fetal liver. The principal evidence suggesting an alloimmune mechanism comes from the observation that the risk of occurrence in a gestation subsequent to one ending in an affected baby is as high as 90%.

Synopsis

 neonatal liver failure
 neonatal diabetes (21284338, 20662354)

Etiology

 fetal alloimmunization (15861012)

• congenital alloimmune hepatitis
• maternal lupus antibodies
• maternal autoantibodies against Ro/SS-A and La/SS-B ribonucleoproteins (8213678)

 hematological anomalies

• Rhesus-incompatibility
• ABO-incompatibility
• congenital hemolysis
• anti-phospholipid syndrome

 fetal infections

• fetal bacterial infections
• amnion infection syndrome
• fetal viral infections
  • fetal CMV infection (1325409)

 undefined familial condition

• autosomal recessive inheritance
• mitochondrial inheritance
• gonadal mosaicism

 chromosomal anomalies

• trisomy 18
• trisomy 21 (20482801)
  • Down syndrome-associated neonatal transitory myelodysplasia (7669389)
  • trisomy 21-associated neonatal hemochromatosis (20482801)

 neonatal acute myeloproliferative disease

 genetic metabolic diseases

• abnormal bile acid metabolism (9285385)
• congenital defects in bile acid synthesis (CBAS2) (delta-4-3-oxosteroid 5 beta-reductase deficiency) (MIM.235555) (9285385, 8301429)

 cardiovascular anomalies

• cardiac malformations
• patent ductus venosus (19458947)
• hepatic hemangioma (18206468)

 digestive anomalies

• duodenal atresia (7758532)
• meconial ileus (11700892)
• gastroschisis (18338135)

 malformative syndromes or malformations

• cardiac malformations
• patent ductus venosus (19458947)
• Martinez-Frias syndrome (intestinal atresia, biliary atresia, diabetes mellitus) (19887127)
• duodenal atresia (7758532)
• multiple malformations (8010353)

 miscellaneous associations

• renal tubular dysgenesis (19809376, 14677054, 9688768, 8066004)
• hypocalvaria (9688768)
• congenital generalized infantile myofibromatosis (11196755)
• neonatal hyperphenylalaninemia and renal tubulopathy (16182582)

Differential diagnosis

 neonatal or infantile hemophagocytic syndrome with liver failure (10347280)

Treatment

There is no effective treatment for neonatal hemochromatosis (NH).

Thus, treatment options are limited, and survival rates with medical therapy are generally recorded as being @<@20%.

Orthotopic liver transplantation (OLT) has been applied, but with
substantial difficulty in this clinical scenario.

More effective medical therapy is clearly needed for newborns with this devastating disease.

Treatment of women at risk for having an affected baby with high-dose
intravenous immunoglobulin (IVIG) reduces the occurrence of having a severely affected baby.

This proof of concept that therapy directed at the immune mechanism of NH can prevent the disease in utero led to the hypothesis that the same approach could alter the course of already established disease
postnatally.

Case records

 Case 10120

See also

 neonatal acute hepatic failure
 neonatal massive hepatic necrosis
 neonatal hepatitis

Reviews

 Whitington PF, Malladi P. Neonatal hemochromatosis: is it an alloimmune disease? J Pediatr Gastroenterol Nutr. 2005 May;40(5):544-9. PMID: 15861012

 Goyal R, Pattari SK, Kakkar N, Radotra BD, Narang A. Neonatal hemochromatosis with massive hepatic necrosis. Fetal Pediatr Pathol. 2004 Sep-Dec;23(5-6):345-50. PMID: 16137172

 Knisely AS, Mieli-Vergani G, Whitington PF. Neonatal hemochromatosis. Gastroenterol Clin North Am. 2003 Sep;32(3):877-89, vi-vii. PMID: 14562579

 Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics. 2001 Oct;108(4):960-4. PMID: 11581451

 Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis. Shneider BL, Setchell KD, Whitington PF, Neilson KA, Suchy FJ. J Pediatr. 1994 Feb;124(2):234-8. PMID: 8301429

 Kershisnik MM, Knisely AS, Sun CC, Andrews JM, Wittwer CT. Cytomegalovirus infection, fetal liver disease, and neonatal hemochromatosis. Hum Pathol. 1992 Sep;23(9):1075-80. PMID: 1325409

 Ruchelli ED, Uri A, Dimmick JE, Bove KE, Huff DS, Duncan LM, Jennings JB, Witzleben CL. Severe perinatal liver disease and Down syndrome: an apparent relationship. Hum Pathol. 1991 Dec;22(12):1274-80. PMID: 1836197

 Siafakas, C. G., Jonas, M. M., Perez-Atayde, A. R. Abnormal bile acid metabolism and neonatal hemochromatosis: a subset with poor prognosis. J. Pediat. Gastroent. Nutr. 25: 321-326, 1997. [PubMed: 9285385]

 Witzleben CL, Uri A. Perinatal hemochromatosis: entity or end result? Hum Pathol. 1989 Apr;20(4):335-40. PMID: 2467869

 A.S. Knisely, G. Mieli-Vergani and P.F. Whitington, Neonatal hemochromatosis, Gastroenterol Clin North Am 32 (2003), pp. 877–889.

 K.F. Murray and K.V. Kowdley, Neonatal hemochromatosis, Pediatrics 108 (2001), pp. 960–964.

 P.F. Whitington, Fetal and infantile hemochromatosis, Hepatology 43 (2006), pp. 654–660.

 D.M. Flynn, N. Mohan, P. McKiernan, S. Beath, J. Buckels and D. Mayer et al., Progress in treatment and outcome for children with neonatal haemochromatosis, Arch Dis Child Fetal Neonatal Ed 88 (2003), pp. F124–F127.

References

 Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn. Martinovici D, Ransy V, Serge Eijnden V, Ridremont C, Pardou A, Cassart M, Avni F, Donner C, Lingier P, Mathieu A, Gulbis B, De Brouckère V, Cnop M, Abramowicz M, Désir J. Eur J Med Genet. 2009 Nov 1. PMID: 19887127

 Relationship of Proximal Renal Tubular Dysgenesis and Fetal Liver Injury in Neonatal Hemochromatosis. Bonilla SF, Melin-Aldana H, Whitington PF. Pediatr Res. 2009 Oct 5. PMID: 19809376

 Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin. Rand EB, Karpen SJ, Kelly S, Mack CL, Malatack JJ, Sokol RJ, Whitington PF. J Pediatr. 2009 Oct;155(4):566-71. PMID: 19560784

 Neonatal hemochromatosis and patent ductus venosus: clinical course and diagnostic pitfalls. Tsai A, Paltiel HJ, Sena LM, Kim HB, Fishman SJ, Alomari AI. Pediatr Radiol. 2009 Aug;39(8):823-7. PMID: 19458947

 Siafakas, C. G., Jonas, M. M., Perez-Atayde, A. R. Abnormal bile acid metabolism and neonatal hemochromatosis: a subset with poor prognosis. J. Pediat. Gastroent. Nutr. 25: 321-326, 1997. [PubMed: 9285385]

 Neonatal hemochromatosis: a case report. Pearson L, Bissinger R, Romero KR. Adv Neonatal Care. 2009 Apr;9(2):72-6. PMID: 19363327

 F. Rodrigues, M. Kallas, R. Nash, P. Cheeseman, L. D’Antiga and M. Rela et al., Neonatal hemochromatosis: medical treatment vs transplantation: the king’s experience, Liver Transpl 11 (2005), pp. 1417–1424.

 L. Sigurdsson, J. Reyes, S.A. Kocoshis, T.W. Hansen, J. Rosh and A.S. Knisely, Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies, J Pediatr Gastroenterol Nutr 26 (1998), pp. 85–89.

 S.S. Sundaram, E.M. Alonso and P.F. Whitington, Liver transplantation in
neonates, Liver Transpl 9 (2003), pp. 783–788.

 P.F. Whitington, Neonatal hemochromatosis: a congenital alloimmune hepatitis, Semin Liver Dis 27 (2007), pp. 243–250.

 A.L. Kelly, P.W. Lunt, F. Rodrigues, P.J. Berry, D.M. Flynn and P.J. McKiernan et al., Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism, J Med Genet 38 (2001), pp. 599–610.

 P.F. Whitington and S. Kelly, Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin, Pediatrics 121 (2008), pp. e1615–e1621.

 P.F. Whitington and J.U. Hibbard, High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis, Lancet 364 (2004), pp. 1690–1698.

 P. Durand, D. Debray, R. Mandel, C. Baujard, S. Branchereau and F. Gauthier et al., Acute liver failure in infancy: a 14-year experience of a pediatric liver transplantation center, J Pediatr 139 (2001), pp. 871–876.

 E. Grabhorn, A. Richter, M. Burdelski, X. Rogiers and R. Ganschow, Neonatal hemochromatosis: long-term experience with favorable outcome, Pediatrics 118 (2006), pp. 2060–2065.

 T. Heffron, T. Pillen, D. Welch, M. Asolati, G. Smallwood and P. Hagedorn et al., Medical and surgical treatment of neonatal hemochromatosis: single center experience, Pediatr Transplant 11 (2007), pp. 374–378.

 R.H. Squires Jr., B.L. Shneider, J. Bucuvalas, E. Alonso, R.J. Sokol and M.R. Narkewicz et al., Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group, J Pediatr 148 (2006), pp. 652–658.

 A.M. Hayes, D. Jaramillo, H.L. Levy and A.S. Knisely, Neonatal
hemochromatosis: diagnosis with MR imaging, AJR Am J Roentgenol 159 (1992), pp. 623–625.

 I.W. Udell, N.R. Barshes, T. Voloyiannis, T.C. Lee, S.J. Karpen and B.A.
Carter et al., Neonatal hemochromatosis: radiographical and histological signs, Liver Transpl 11 (2005), pp. 998–1000.

 A.S. Knisely, P.A. O’Shea, J.F. Stocks and J.E. Dimmick, Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis, J Pediatr 113 (1988), pp. 871–874.

 S.R. Smith, B.L. Shneider, M. Magid, G. Martin and M. Rothschild, Minor
salivary gland biopsy in neonatal hemochromatosis, Arch Otolaryngol Head Neck Surg 130 (2004), pp. 760–763.

 I. Shamieh, P.K. Kibort, F.J. Suchy and D.K. Freese, Antioxidant therapy for neonatal iron storage disease (NISD), Abstract. Pediatr Res 33 (1993), p. 109A.

 P. Vohra, C. Haller, S. Emre, M. Magid, I. Holzman and M.Q. Ye et al.,
Neonatal hemochromatosis: the importance of early recognition of liver failure, J Pediatr 136 (2000), pp. 537–541.

 M.A. Leonis and W.F. Balistreri, Neonatal hemochromatosis: it’s OK to say “NO” to antioxidant-chelator therapy, Liver Transpl 11 (2005), pp. 1323–1325.

 M.M. Silver, L.S. Valberg, E. Cutz, L.D. Lines and M.J. Phillips, Hepatic
morphology and iron quantitation in perinatal hemochromatosis: comparison with a large perinatal control population, including cases with chronic liver disease, Am J Pathol 143 (1993), pp. 1312–1325.

 J. Bernuau, B. Rueff and J.P. Benhamou, Fulminant and subfulminant liver
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